Azinyloxy, and phenoxy-diaryl-carboxylic acid derivatives, their preparation and use as mixed ETA/ETB endothelin receptor antagonists

ABSTRACT

The invention relates to carboxylic acid derivatives of the formula Iwhere the radicals have the meanings stated in the description, and to their use as drugs.

The present invention relates to novel carboxylic acid derivatives,their preparation and use.

Endothelin is a peptide which consists of 21 amino acids and issynthesized and released by vascular endothelium. Endothelin exists inthree isoforms, ET-1, ET-2 and ET-3. “Endothelin” or “ET” hereinaftermeans one or all isoforms of endothelin. Endothelin is a potentvasoconstrictor and has a great effect on vessel tone. It is known thatthis vasoconstriction is caused by binding of endothelin to its receptor(Nature, 332, 1988, 411-415; FEBS Letters, 231, 1988, 440-444 andBiochem. Biophys. Res. Commun., 154, 1988, 868-875).

Increased or abnormal release of endothelin causes persistentvasoconstriction in peripheral, renal and cerebral vessels, which maylead to disorders. As reported in the literature, endothelin is involvedin a number of disorders. These include: hypertension, acute myocardialinfarct, pulmonary hypertension, Raynaud's syndrome, cerebralvasospasms, stroke, benign prostate hypertrophy, atherosclerosis andasthma (J. Vascular Med. Biology 2, (1990) 207, J. Am. Med. Association264, (1990) 2868, Nature 344, (1990) 114, N. Engl. J. Med. 322, (1989)205, N. Engl. J. Med. 328, (1993) 1732, Nephron 66, (1994) 373, Stroke25, (1994) 904, Nature 365, (1993) 759, J. Mol. Cell. Cardiol. 27,(1995) A234; Cancer Research 56, (1996) 663).

At least two endothelin receptor subtypes, ET_(A) and ET_(B) receptors,have been described in the literature (Nature 348, (1990) 730, Nature348, (1990) 732). Accordingly, substances which inhibit the binding ofendothelin to the two receptors ought to antagonize the physiologicaleffects of endothelin and therefore be valuable drugs.

WO 96/11914 describes carboxylic acid derivatives which, however, bindwith high affinity to the ET_(A) receptor and with considerably lessaffinity to the ET_(B) receptor (called ET_(A)-specific antagonists).

ET_(A)-specific antagonists mean here those antagonists whose affinityfor the ET_(A) receptor is at least twenty times higher than theiraffinity for the ET_(B) receptor.

It is an object of the present invention to provide endothelin receptorantagonists which bind with approximately the same affinity to theET_(A) and ET_(B) receptors (called mixed antagonists).

Approximately the same affinity for the receptors means that theET_(A):ET_(B) affinity ratio is greater than 0.1 and less than 20,preferably less than 10.

We have found that this object is achieved by carboxylic acidderivatives of the formula I

where R¹ is tetrazole [sic] or a group

where R has the following meaning:

a) a radical OR⁷ where R⁷ is:

hydrogen, the cation of an alkali metal, the cation of an alkaline earthmetal, a physiologically tolerated organic ammonium ion such asC₁-C₄-alkylammonium or the ammonium ion;

C₃-C₈-cycloalkyl, C₁-C₈-alkyl, CH₂-phenyl which can be substituted byone or more of the following radicals: halogen, nitro, cyano,C₁-C₄-alkyl, C₁-C₄-haloalkyl, hydroxyl, C₁-C₄-alkoxy, mercapto,C₁-C₄-alkylthio, amino, carboxyl, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂;

C₃-C₆-alkenyl or C₃-C₆-alkynyl, it being possible for these groups inturn to carry one to five halogen atoms;

R⁷ can furthermore be a phenyl radical which may carry one to fivehalogen atoms and/or one to three of the following radicals, nitro,cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, hydroxyl, C₁-C₄-alkoxy, mercapto,C₁-C₄-alkylthio, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂;

b) a 5-membered heteroaromatic system which is linked via a nitrogenatom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which maycarry one to two halogen atoms or one to two C₁-C₄-alkyl or one to twoC₁-C₄-alkoxy groups;

c) a group

 where k is 0, 1 and 2, p is 1, 2, 3 and 4 and R⁸ is

C₁-C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl or phenylwhich can be substituted by one or more, eg. one to three, of thefollowing radicals: halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl,hydroxyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, mercapto, amino, carboxyl,NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂;

d) a radical

 in which R⁹ is:

C₁-C₄-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₈-cycloalkyl,C₁-C₄-haloalkyl, it being possible for these radicals to carry aC₁-C₄-alkoxy, C₁-C₄-alkylthio and/or a phenyl radical as mentioned underc);

phenyl, unsubstituted or substituted, in particular as mentioned above,

e) R¹ can furthermore be

 where R¹³ and R¹⁴ can be identical or different and have the followingmeanings:

hydrogen, C₁-C₈-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-alkenyl, C₃-C₈-alkynyl,benzyl, phenyl which may carry one to five halogen atoms and/or one tothree of the following radicals: nitro, cyano, C₁-C₄-alkyl,C₁-C₄-haloalkyl, hydroxyl, C₁-C₄-alkoxy, mercapto, C₁-C₄-alkylthio,amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂,

or R¹³ and R¹⁴ together form a C₄-C₇-alkylene chain which is closed toform a ring and which may be substituted by C₁-C₄-alkyl and in which analkylene group may be replaced by oxygen, sulfur or nitrogen, such as—(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₂—O—(CH₂)₂—, —(CH₂)₇—,—CH₂—S—(CH₂)₂—, —CH₂—NH—(CH₂)₂—, —(CH₂)₂—N—(CH₂)₂—;

R² hydrogen, hydroxyl, NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, halogen,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-hydroxyalkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio, orCR² is linked to CR¹⁰ as indicated below to give a 5- or 6-memberedring.

X nitrogen or methine.

Y nitrogen or methine.

Z nitrogen or CR¹⁰, where R¹⁰ is hydrogen or C₁-C₄-alkyl, or CR¹⁰ formstogether with CR² or CR³ a 5- or 6-membered alkylene or alkenylene ringwhich may be substituted by one or two C₁-C₄-alkyl groups and in whichin each case one or more methylene groups can be replaced by oxygen,sulfur, —NH or N(C₁-C₄-alkyl)₂.

At least one of the ring members X, Y or Z is nitrogen.

R³ hydrogen, hydroxyl, NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, halogen,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-hydroxyalkyl or C₁-C₄-alkylthio,or CR³ is linked to CR¹⁰ as indicated above to give a 5- or 6-memberedring.

R⁴ and R⁵ (which may be identical or different):

phenyl or naphthyl, which may be substituted by one or more of thefollowing radicals: halogen, nitro, cyano, hydroxyl, mercapto,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₁-C₄-hydroxyalkyl, C₂-C₄-alkynyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, phenoxy, carboxyl, C₁-C₄-haloalkoxy,C₁-C₄-alkylthio, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂ or phenyl whichcan be substituted one or more times, eg. one to three times by halogen,nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy or C₁-C₄-alkylthio; or phenyl or naphthyl, which arelinked together in the ortho positions by a direct linkage, a methylene,ethylene or ethenylene group, an oxygen or sulfur atom or an SO₂, NH orN-alkyl group;

C₃-C₈-cycloalkyl.

R⁶ C₃-C₈-Cycloalkyl, it being possible for these radicals in each caseto be substituted one or more times by: halogen, hydroxyl, mercapto,carboxyl, nitro, cyano, C₁-C₄-alkoxy, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₂-C₄-alkynyl, C₃-C₆-alkenyloxy, C₃-C₆-alkynyloxy, C₁-C₄-alkylthio,C₁-C₄-haloalkoxy, C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₃-C₈-alkyl-carbonylalkyl, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, or phenylwhich can be substituted one or more times, eg. one to three times, byhalogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy or C₁-C₄-alkylthio;

phenyl or naphthyl, each of which can be substituted by one or more ofthe following radicals: halogen, R¹⁵, nitro, mercapto, carboxyl, cyano,hydroxyl, amino, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl,C₃-C₆-alkenyloxy, C₁-C₄-haloalkyl, C₃-C₆-alkynyloxy,C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, NH(C₁-C₄-alkyl),N(C₁-C₄-alkyl)₂, dioxomethylene [sic], dioxoethylene [sic] or phenylwhich can be substituted one or more times, eg. one to three times, byhalogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy or C₁-C₄-alkylthio;

a five- or six-membered heteroaromatic system containing one to threenitrogen atoms and/or one sulfur or oxygen atom, which may carry one tofour halogen atoms and/or one to two of the following radicals:C₁-C₄-alkyl, C₂-C₄-alkenyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, phenyl or phenoxy it being possiblefor the phenyl radicals in turn to carry one to five halogen atomsand/or one to three of the following radicals: C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio;

R¹⁵ is C₁-C₄-alkyl, C₁-C₄-alkylthio or C₁-C₄-alkoxy which carry one ofthe following radicals: hydroxyl, carboxyl, amino, NH(C₁-C₄-alkyl),N(C₁-C₄-alkyl)₂, carboxamide [sic] or CON(C₁-C₄-alkyl)₂;

W sulfur or oxygen.

Q a spacer whose length corresponds to that of a C₂-C₄ chain. Thefunction of Q is to produce a defined distance between the groups R⁶ andW in the compounds of the formula I. The distance should correspond tothe length of a C₂-C₄-alkyl chain. This can be achieved by a largenumber of chemical radicals, for example with C₂-C₄-alkyl,C₃-C₄-alkenyl, C₃-C₄-alkynyl, —S—CH₂—CH₂—, —O—CH₂—CH₂—, —N—CO—CH₂—O—, itbeing possible for each of these radicals to be substituted one or moretimes by: halogen, hydroxyl, mercapto, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₂-C₄-alkynyl, carboxyl, nitro, cyano, C₁-C₄-alkoxy, C₃-C₆-alkenyloxy,C₃-C₆-alkynyloxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy,C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₃-C₈-alkylcarbonylalkyl,NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, phenyl which can be substituted one ormore times, eg. one to three times, by halogen, nitro, cyano,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy orC₁-C₄-alkylthio.

Or the spacer Q is part of a 5-7-membered heterocyclic or carbocyclicring to which R⁶ is fused.

The following definitions apply thereto and hereinafter:

An alkali metal is, for example, lithium, sodium, potassium;

An alkaline earth metal is, for example, calcium, magnesium, barium;

C₃-C₈-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl;

C₁-C₄-haloalkyl can be linear or branched, such as, for examplefluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl,dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl;

C₁-C₄-haloalkoxy can be linear or branched, such as, for example,difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy,1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy,2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy orpentafluoroethoxy;

C₁-C₄-alkyl can be linear or branched, such as, for example, methyl,ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butylor 2-butyl;

C₂-C₄-alkenyl can be linear or branched, such as, for example, ethenyl,1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl,1-butenyl or 2-butenyl;

C₂-C₄-alkynyl can be linear or branched, such as, for example, ethynyl,1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;

C₁-C₄-alkoxy can be linear or branched, such as, for example, methoxy,ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy,2-methylpropoxy or 1,1-dimethylethoxy;

C₃-C₆-alkenyloxy can be linear or branched, such as, for example,allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;

C₁-C₄-hydroxyalkyl can be linear or branched, such as, for example,hydroxymethyl, 1-hydroxyether-2-yl,

C₃-C₆-alkynyloxy can be linear or branched, such as, for example,2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;

C₁-C₄-alkylthio can be linear or branched, such as, for example,methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio,1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;

C₁-C₄-alkylcarbonyl can be linear or branched, such as, for example,acetyl, ethylcarbonyl or 2-propylcarbonyl;

C₁-C₄-alkoxycarbonyl can be linear or branched, such as, for example,methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl orn-butoxycarbonyl;

C₃-C₈-alkylcarbonylalkyl can be linear or branched, such as, forexample, 2-oxo-1-propyl, 3-oxo-1-butyl or 3-oxo-2-butyl

C₁-C₈-alkyl can be linear or branched, such as, for example,C₁-C₄-alkyl, pentyl, hexyl, heptyl or octyl;

halogen is, for example fluorine, chlorine, bromine, iodine.

The invention furthermore relates to those compounds from whichcompounds of the formula I can be liberated (called prodrugs).

Preferred prodrugs are those with which release takes place underconditions like those prevailing in certain compartments of the body,eg. in the stomach, intestine, bloodstream, liver.

The compounds, and the intermediates for preparing them, such as II, IIIand IV, may have one or more asymmetrically substituted carbon atoms.Such compounds can be in the form of pure enantiomers or purediastereomers or mixture thereof. An enantiomerically pure compound ispreferably used as active substance.

The invention furthermore relates to the use of the abovementionedcarboxylic acid derivatives for producing drugs, in particular forproducing inhibitors of ET_(A) and ET_(B) receptors. The compoundsaccording to the invention are particularly suitable as mixedantagonists as defined at the outset.

Compounds of the formula IV where Z is sulfur or oxygen can be preparedas described in WO 96/11914, also in enantiomerically pure form.

Compounds of the formula III are known or can be synthesized, forexample, by reducing the corresponding carboxylic acids or estersthereof or by other conventional methods.

Carboxylic acid derivatives of the formula IV [sic] can also be preparedby reacting a compound of the formula IVa with an alcohol or thiol ofthe formula VII with acid catalysis.

The indicated radicals have the following meanings:

R¹ has the meaning indicated for formula I

R¹⁶ and R¹⁷, which may be identical or different, hydrogen or alkyl,alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, in each caseunsubstituted or substituted,

R¹⁸ hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl,in each case unsubstituted or substituted,

R¹⁹ hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl,in each case unsubstituted or substituted,

and the radicals preferably have the following meanings:

R¹ COOR⁷

R¹⁶ and R¹⁷, which may be identical or different, alkyl, phenyl,naphthyl, cycloalkyl, in each case unsubstituted or substituted,

R¹⁸ alkyl, phenyl, cycloalkyl, in each case unsubstituted orsubstituted,

R¹⁹ alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, in each caseunsubstituted or substituted,

and the following radicals are particularly preferred:

R¹ COOCH₃

R¹⁶ R⁴

R¹⁷ R⁵

R¹⁸ alkyl, unsubstituted or substituted, in particular methyl

R¹⁹ R⁶—Q.

The carboxylic acid derivatives of the formula IV can be prepared bythis process by reacting a compound of the formula IVa with an alcoholor thiol of the formula III with acid catalysis

For this purpose, the compounds IVa and III are mixed without diluent orin a solvent which is inert for this reaction, and catalytic amounts ofan acid such as p-toluenesulfonic acid are added. Examples of inertsolvents are methylene chloride, benzene or toluene. Also suitable arethose inert solvents which form an azeotrope with the alcohol R¹⁸OH. Inthe case of methanol (R¹⁸═CH₃), examples of these are chloroform ormethyl acetate.

The reaction mixture is then stirred at from room temperature to theboiling point of the solvent. The resulting alcohol R¹⁸OH is removed bydistilling out or reducing the pressure. This method is also suitablefor preparing enantiomerically pure IV if the IVa starting material isenantiomerically pure.

Compounds of the formula IVa are known and are described, for example,in WO 96/11914.

The compounds according to the invention in which the substituents havethe meanings stated for formula I can be prepared, for example, byreacting the carboxylic acid derivatives of the formula IV in which thesubstituents have the stated meanings with compounds of the formula V.

In formula V, R¹¹ is halogen or R¹²—SO₂— where R¹² can be C₁-C₄-alkyl,C₁-C₄-haloalkyl or phenyl. In addition, at least one of the ring membersX or Y or Z is nitrogen. The reaction preferably takes place in an inertsolvent or diluent with the addition of a suitable base, ie. a basewhich deprotonates the intermediate IV, at a temperature in the rangefrom room temperature to the boiling point of the solvent.

Compounds of type I with R¹=COOH can furthermore be obtained directly bydeprotonating the intermediate IV where R¹ is COOH with two equivalentsof a suitable base, and reacting with compounds of the formula V. Thisreaction also takes place in an inert solvent and at a temperature inthe range from room temperature to the boiling point of the solvent.

Examples of such solvents and diluents are aliphatic, alicyclic andaromatic hydrocarbons, each of which may be chlorinated, such as hexane,cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene,methylene chloride, chloroform, carbon tetrachloride, ethyl chloride andtrichloroethylene, ethers such as diisopropyl ether, dibutyl ether,methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran,nitriles such as acetonitrile and propionitrile, amides such asdimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxidesand sulfones, for example dimethyl sulfoxide and sulfolane.

Compounds of the formula V are known, and in some cases can be bought orprepared in a conventional way.

The base which can be used is an alkali metal or alkaline earth metalhydride such as sodium hydride, potassium hydride or calcium hydride, acarbonate such as an alkali metal carbonate, eg. sodium or potassiumcarbonate, an alkali metal or alkaline earth metal hydroxide such assodium or potassium hydroxide, an organometallic compound such asbutyllithium or an alkali metal amide such as lithium diisopropylamideor lithium amide.

Compounds of the formula I can also be prepared by starting from thecorresponding carboxylic acids, ie. compounds of the formula I where R¹is COOH, and converting first them in a conventional way into anactivated form, such as a halide, an anhydride or imidazolide, and thenreacting the latter with an appropriate hydroxyl compound HOR⁷. Thisreaction can be carried out in conventional solvents and often requiresthe addition of a base, in which case those mentioned above aresuitable. These two steps can also be simplified, for example, byallowing the carboxylic acid to act on the hydroxyl compound in thepresence of a dehydrating agent such as a carbodiimide.

It is also possible to prepare compounds of the formula I by startingfrom the salts of the appropriate carboxylic acids, ie. from compoundsof the formula I where R¹ is COR and R is OM [sic] where M can be analkali metal cation or the equivalent of an alkaline earth metal cation.These salts can be reacted with many compounds of the formula R—A whereA is a conventional nucleofugic leaving group, for example halogens suchas chlorine, bromine, iodine, or aryl- or alkylsulfonyl which isunsubstituted or substituted by halogen, alkyl or haloalkyl, such astoluenesulfonyl and methylsulfonyl, or another equivalent leaving group.Compounds of the formula R—A with a reactive substituent A are known orcan easily be obtained with general expert knowledge. This reaction canbe carried out in conventional solvents and is advantageously undertakenwith the addition of a base, in which case those mentioned above aresuitable.

In some cases it is necessary to use generally known protective grouptechniques to prepare compounds I according to the invention. If, forexample, R⁶ is to be 4-hydroxyphenyl, it is possible first to protectthe hydroxyl group as benzyl ether, which is then cleaved at a suitablestage in the reaction sequence.

Compounds of the formula I where R¹ is tetrazole [sic] can be preparedas described in WO 96/11914.

With a view to the biological effect, preferred carboxylic acidderivatives of the formula I, both as pure enantiomers or purediastereomers or as mixture thereof, are those where the substituentshave the following meanings:

R² hydrogen, hydroxyl, halogen, N(C₁-C₄-alkyl)₂, C₁-C₄-alkyl,C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, or CR²is linked to CR¹⁰ as indicated below to give a 5- or 6-membered ring;

X nitrogen or methine;

Y nitrogen or methine;

Z nitrogen or CR¹⁰, where R¹⁰ is hydrogen or C₁-C₄-alkyl, or CR¹⁰ formstogether with CR² or CR³ a 5- or 6-membered alkylene or alkenylene ringwhich can be substituted by one or two methyl groups and in which, ineach case, one methylene group can be replaced by oxygen or sulfur, suchas —CH₂—CH₂—O—, —CH₂—CH₂—CH₂—O—, —CH═CH—O—, —CH═CH—CH₂O—,—CH(CH₃)—CH(CH₃)—O—, —CH=C(CH₃)—O—, —C(CH₃)═C(CH₃)—O—, or—C(CH₃)═C(CH₃)—S;

At least one of the ring members X, Y or Z is nitrogen.

R³ hydrogen, hydroxyl, halogen, N(C₁-C₄-alkyl)₂, C₁-C₄-alkyl,C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, or CR³is linked to CR¹⁰ as indicated above to give a 5- or 6-membered ring;

R⁴ and R⁵ (which can be identical or different):

phenyl or naphthyl, which can be substituted by one or more of thefollowing radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino,C₁-C₄-alkyl, C₁-C₄-haloalkyl, carboxyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,phenoxy, C₁-C₄-alkylthio, NH(C₁-C₄-alkyl) or N(C₁-C₄-alkyl)₂ or phenylwhich can be substituted one or more times, eg. one to three times, byhalogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy or C₁-C₄-alkylthio; or

phenyl or naphthyl, which are connected together in the ortho positionsby a direct linkage, a methylene, ethylene or ethenylene group, anoxygen or sulfur atom or an SO₂—, NH— or N-alkyl group,

C₃-C₈-cycloalkyl;

R⁶ C₃-C₈-cycloalkyl, it being possible for these radicals in each caseto be substituted one or more times by: halogen, hydroxyl, mercapto,carboxyl, nitro, cyano, C₁-C₄-alkoxy, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₂-C₄-alkynyl, C₃-C₆-alkenyloxy, C₃-C₆-alkynyloxy, C₁-C₄-alkylthio,C₁-C₄-haloalkoxy, C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl,NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂ or phenyl which can be substituted oneor more times, eg. one to three times, by halogen, nitro, cyano,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy orC₁-C₄-alkylthio;

phenyl or naphthyl, each of which can be substituted by one or more ofthe following radicals: halogen, R¹⁵, nitro, mercapto, carboxyl, cyano,hydroxyl, amino, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl,C₃-C₆-alkenyloxy, C₁-C₄-haloalkyl, C₃-C₆-alkynyloxy,C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, NH(C₁-C₄-alkyl),N(C₁-C₄-alkyl)₂, dioxomethylene [sic], dioxoethylene [sic] or phenylwhich can be substituted one or more times, eg. one to three times, byhalogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy or C₁-C₄-alkylthio;

a five- or six-membered heteroaromatic system containing one to threenitrogen atoms and/or one sulfur or oxygen atom, which can carry one tofour halogen atoms and/or one to two of the following radicals:C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenylradicals in turn can carry one to five halogen atoms and/or one to threeof the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio;

R¹⁵ methyl, ethyl, methoxy or ethoxy which carry one of the followingradicals: hydroxyl, carboxyl, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂,carboxamide [sic] or CON(C₁-C₄-alkyl)₂;

W sulfur or oxygen;

Q C₂-C₄-alkyl, C₃-C₄-alkenyl, C₃-C₄-alkynyl, —S—CH₂—CH₂—, —O—CH₂—CH₂—,it being possible for each of these radicals to be substituted one ormore times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano,C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy,C₁-C₄-alkoxycarbonyl, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂ or phenyl whichcan be substituted one or more times, eg. one to three times, byhalogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy or C₁-C₄-alkylthio

or Q forms together with R⁶ the following ring systems: 2-indanyl,3-indanyl, 1,2,3,4-tetrahydro-2-naphthyl, 1,2,3,4-tetrahydro-3-naphthyl,it being possible for the phenyl rings in each case to be substitutedby: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C₁-C₄-alkoxy,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₃-C₆-alkenyloxy,C₃-C₆-alkynyloxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy,C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl, amino, NH(C₁-C₄-alkyl),N(C₁-C₄-alkyl)₂ or phenyl.

Particularly preferred compounds of the formula I, both as pureenantiomers and pure diastereomers or mixtures thereof, are those wherethe substituents have the following meanings:

R² trifluoromethyl, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, or CR²is linked to CR¹⁰ as indicated below to give a 5- or 6-membered ring;

X nitrogen or methine;

Y nitrogen or methine;

Z nitrogen or CR¹⁰ where R¹⁰ is hydrogen or C₁-C₄-alkyl, or CR¹⁰ formstogether with CR² or CR³ a 5- or 6-membered alkylene or alkenylene ringwhich can be substituted by one or two methyl groups and in which ineach case a methylene group can be replaced by oxygen or sulfur, such as—CH₂—CH₂—O—, —CH₂—CH₂—CH₂—O—, —CH═CH—O—, —CH═CH—CH₂O—,—CH(CH₃)—CH(CH₃)—O—, —CH=C(CH₃)—O—, —C(CH₃)═C(CH₃)—O—, or—C(CH₃)═C(CH₃)—S;

At least one of the ring members X, Y or Z is nitrogen

R³ trifluoromethyl, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, or CR³is linked to CR¹⁰ as indicated above to give a 5- or 6-membered ring;

R⁴ and R⁵ (which can be identical or different):

phenyl or naphthyl, which can be substituted by one or more of thefollowing radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy,C₁-C₄-alkylthio, NH(C₁-C₄-alkyl) or N(C₁-C₄-alkyl)₂ or phenyl which canbe substituted one or more times, eg. one to three times, by halogen,nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy or C₁-C₄-alkylthio; or

phenyl or naphthyl, which are connected together in the ortho positionsby a direct linkage, a methylene, ethylene or ethenylene group, anoxygen or sulfur atom or an SO₂—, NH— or N-alkyl group

C₅-C₇-cycloalkyl;

R⁶ C₅-C₇-cycloalkyl, it being possible for these radicals in each caseto be substituted one or more times by: C₁-C₄-alkoxy,

C₁-C₄-alkyl, C₁-C₄-alkylthio, halogen, hydroxyl, carboxyl, cyano,trifluoromethyl, acetyl, or phenyl which can be substituted one or moretimes, eg. one to three times, by halogen, cyano, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio;

phenyl or naphthyl, each of which can be substituted by one or more ofthe following radicals: halogen, R¹⁵, nitro, mercapto, carboxyl, cyano,hydroxyl, amino, C₁-C₄-alkyl, C₁-C₄-haloalkyl, acetyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy,C₁-C₄-alkylthio, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, dioxomethylene [sic],dioxoethylene [sic] or

phenyl which can be substituted one or more times, eg. one to threetimes, by halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio;

a five- or six-membered heteroaromatic system containing one to threenitrogen atoms and/or one sulfur or oxygen atom, which can carry one tofour halogen atoms and/or one to two of the following radicals:C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, trifluoromethoxy,C₁-C₄-alkylthio, phenyl or phenoxy, it being possible for the phenylradicals in turn to carry one to five halogen atoms and/or one to threeof the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio;

R¹⁵ methoxy or ethoxy which carry one of the following radicals:hydroxyl, carboxyl, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, carboxamide[sic] or CON(C₁-C₄-alkyl)₂;

W sulfur or oxygen;

Q C₂-C₄-alkyl, C₃-C₄-alkenyl, C₃-C₄-alkynyl, —S—CH₂—CH₂—, —O—CH₂—CH₂—,it being possible for each of these radicals to be substituted one ormore times by: halogen, hydroxyl, mercapto, carboxyl, C₁-C₄-alkyl,C₁-C₄-alkoxy, C₁-C₄-alkylthio, or phenyl which can be substituted one ormore times, eg. one to three times, by halogen, nitro, cyano,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy orC₁-C₄-alkylthio

or Q forms together with R⁶ the following ring systems: 2-indanyl,3-indanyl, 1,2,3,4-tetrahydro-2-naphthyl, 1,2,3,4-tetrahydro-3-naphthyl,it being possible for the phenyl rings in each case to be substitutedby: halogen, hydroxyl, mercapto, carboxyl, cyano, C₁-C₄-alkoxy,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₃-C₆-alkenyloxy,C₃-C₆-alkynyloxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy,C₁-C₄-alkoxycarbonyl, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂ or phenyl.

The compounds of the present invention offer a novel therapeuticpotential for the treatment of hypertension, pulmonary hypertension,myocardial infarct, chronic heart failure, angina pectoris,acute/chronic kidney failure, renal insufficiency, cerebral vasospasms,cerebral ischemia, subarachnoid hemorrhages, migraine, asthma,atherosclerosis, endotoxic shock, endotoxin-induced organ failure,intravascular coagulation, restenosis after angioplasty, benign prostatehyperplasia, kidney failure and hypertension caused by ischemia andintoxication, metastasis and growth of mesenchymal tumors, kidneyfailure induced by contrast agents, pancreatitis, gastrointestinalulcers.

The compounds according to the invention surprisingly also show in somecases an antagonistic action on the neurokinin receptor.

This is particularly true of compounds of the formula I where R¹ is

The invention furthermore relates to combination products consisting ofendothelin receptor antagonists of the formula I and inhibitors of therenin-angiotensin system. Inhibitors of the renin-angiotensin system arerenin inhibitors, angiotensin II antagonists and, in particular,angiotensin converting enzyme (ACE) inhibitors.

The invention further relates to combination products of β blockers andthe abovementioned endothelin receptor antagonists, and of mixedACE/neutral endopeptidase (NEP) inhibitors and the abovementionedendothelin receptor antagonists.

The combination products can be administered in a single pharmaceuticalform or else in spatially separate forms. Administration may take placesimultaneously or sequentially.

The dosage of the combination may be up to the maximum single dose ineach case. However, it is also possible to employ lower doses than inthe single therapy in each case.

These combination products are particularly suitable for the treatmentand prevention of hypertension and its sequelae, and for the treatmentof heart failure.

The good effect of the compounds can be shown in the following tests:

Receptor Binding Studies

Cloned human ET_(A) or ET_(B) receptor-expressing CHO cells wereemployed for binding studies.

Membrane Preparation

The ET_(A) or ET_(B) receptor-expressing CHO cells were grown in DMEMNUT MIX F₁₂ medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAALaboratories GmbH, Linz, No. A15-022), 1 mM glutamine (Gibco No.25030-024), 100 U/ml penicillin and 100 μg/ml streptomycin (Gibco, SigmaNo. P-0781). After 48 hours, the cells were washed with PBS andincubated with 0.05% trypsin-containing PBS at 37° C. for 5 minutes.Neutralization with medium was then carried out, and the cells werecollected by centrifugation at 300×g.

For the membrane preparation, the cells were adjusted to a concentrationof 10₈ cells/ml of buffer (50 mM tris.HCL buffer, pH 7.4) and thendisintegrated by ultrasound (Branson Sonifier 250, 40-70seconds/constant/output 20).

Binding Assays

For the ET_(A) and ET_(B) receptor binding assays, the membranes weresuspended in incubation buffer (50 mM tris-HCl, pH 7,4 with 5 mM MnCl₂,40 μg/ml bacitracin and 0.2% BSA) at a concentration of 50 μg of proteinper assay mixture, and incubated with 25 pM ¹²⁵I-ET₁ (ET_(A) receptorassay) or 25 pM ¹²⁵I-ET₃ (ET_(B) receptor assay) in the presence andabsence of test substance at 25° C. The nonspecific binding wasdetermined with 10⁻⁷ M ET₁. Filtration was carried out after 30 minthrough GF/B glassfiber filters (Whatman, England) in a Skatron cellcollector (Skatron, Lier, Norway) to separate free and bound radioligands, and the filters were washed with ice-cold tris-HCl buffer, pH7.4 with 0.2% BSA. The radioactivity collected on the filters wasquantified using a

Packard 2200 CA liquid scintillation counter.

Testing of the ET antagonists in vivo:

Male SD rats weighing 250-300 g were anesthetized with amobarbital,artificially ventilated, vagotomized and pithed. The carotid artery andjugular vein were catheterized.

Intravenous administration of 1 μg/kg ET1 to control animals led to amarked rise in blood pressure, which persisted for a lengthy period.

The test animals received i.v. injections of the test compounds (1ml/kg) 30 min before administration of ET1. To determine theET-antagonistic properties, the changes in blood pressure in the testanimals were compared with those in the control animals.

Oral testing of the mixed ET_(A) and ET_(B) antagonists:

Normotensive male rats (Sprague Dawley, Janvier) weighing 250-350 g arepretreated orally with the test substances. 80 minutes later, theanimals are anesthetized with urethane, and the carotid artery (formeasuring the blood pressure) and the jugular vein (administration ofbig endothelin/endothelin 1) are catheterized.

After a stabilization period, big endothelin (20 μg/kg, administrationvolume 0.5 ml/kg) or ET1 (0.3 μg/kg, administration volume 0.5 ml/kg) isgiven intravenously. The blood pressure and heartrate are recordedcontinuously for 30 minutes. The marked and long-lasting changes inblood pressure are calculated as area under the curve (AUC). Todetermine the antagonistic effect of the test substances, the AUC forthe animals treated with the substance is compared with the AUC for thecontrol animals.

The compounds according to the invention can be administered orally orparenterally (subcutaneously, intravenously, intramuscularly,intraperitoneally) in a conventional way. Administration may also takeplace with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient andon the mode of administration. As a rule, the daily dose of activesubstance is about 0.5-50 mg/kg of bodyweight on oral administration andabout 0.1-10 mg/kg of bodyweight on parenteral administration.

The novel compounds can be used in conventional solid or liquidpharmaceutical forms, eg. as uncoated or (film-)coated tablets,capsules, powders, granules, suppositories, solutions, ointments, creamsor sprays. These are produced in a conventional way. For this purpose,the active substances can be processed with conventional pharmaceuticalauxiliaries such as tablet binders, bulking agents, preservatives,tablet disintegrants, flow regulators, plasticizers, wetting agents,dispersants, emulsifiers, solvents, release-slowing agents, antioxidantsand/or propellant gases (cf. H. Sucker et al.: PharmazeutischeTechnologie, Thieme-Verlag, Stuttgart, 1991). The administration formsobtained in this way normally contain from 0.1 to 90% by weight ofactive substance.

SYNTHESIS EXAMPLES Example 1

Methyl2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate

7 g (27.5 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate and 5.5 g(30.2 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were dissolved in 20 ml ofdichloromethane and, at room temperature, 5 drops of boron trifluorideetherate were added. The solution was stirred for 2 hours. The solventwas then distilled off, and the residue (10.7 g, 89%) was immediatelyreacted further.

Example 2

2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic Acid

12 g (27.5 mmol) of methyl2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate weredissolved in 110 ml of dioxane, and 55 ml of 1 N NaOH solution wereadded. The mixture was stirred at 80° C. for 2 hours. Water was added tothe mixture, and the aqueous phase was extracted twice with ether. Theaqueous phase was acidified with 1 N aqueous HCl and extracted withether, the organic phase was dried over magnesium sulfate, and thesolvent was distilled off. The residue was recrystallized fromether/n-hexane, and 10.2 g (87%) of colorless crystals were isolated.

Melting point: 133-135° C.

Example 3

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-482)

1 g (2.3 mmol) of2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic acidwas introduced into 10 ml of DMF, and 340 mg of NaH (50% suspension)were added. After the mixture had been stirred for 15 minutes, 526 mg of4-methoxy-6-methyl-2-methylsulfonylpyrimidine were added, and themixture was stirred at room temperature for 3 hours. Water was added tothe mixture, which was then extracted with ether. The aqueous phase wasacidified with 1 N aqueous HCl, extracted with ether and dried overmagnesium sulfate. The solvent was distilled off, the residue waspurified by MPLC, and 655 mg (52%) of colorless powder were isolatedafter recrystallization from ether/n-hexane.

¹H-NMR (200 MHz): 7.2 ppm (10H, m), 6.8 (3H, m), 6.2 (1H, s), 6.18 (1H,s), 3.9 (9H, m), 3.8 (1H, m), 3.7 (1H, m), 2.85 (2H, tr), 2.2 (3H, s).EI-MS: M⁺=544.

Example 4

Methyl 3,3-di(4-Ethylphenyl)-2,3-epoxypropionate

A solution of 15 ml (168 mmol) of methyl chloroacetate and 20 g (84mmol) of 4,4′-diethylbenzophenone in 20 ml of THF was added dropwise toa suspension of 9.1 g (168 mmol) of sodium ethanolate in 80 ml of THF at−10° C. The mixture was warmed to room temperature and stirred for 2hours. The mixture was added to water and extracted with ether. Theorganic phase was washed with sodium bicarbonate solution and citricacid solution and dried over magnesium sulfate, and the solvent wasdistilled off. 15.4 g of a crude oil were isolated and were immediatelyemployed further.

Example 5

Methyl2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di-(4-ethyl-phenyl)propionate

6 g (19.3 mmol) of methyl 3,3-di(4-ethylphenyl)-2,3-epoxypropionate(crude) and 3.52 g (19.3 mmol) of 2-(3,4-dimethoxyphenyl)ethanol weredissolved in 20 ml of dichloromethane and, at room temperature, 5 dropsof boron trifluoride etherate were added. The solution was stirred for1.5 hours. The solvent was then distilled off, and the residue, a paleyellow oil (8.66 g, 91%), was immediately reacted further.

Example 6

2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionicAcid

9.2 g (19.3 mmol) of methyl2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionatewere dissolved in 26 ml of dioxane, and 13 ml of 3 N NaOH solution wereadded. The mixture was stirred at 60° C. for 3 hours. Water was added tothe mixture, and the aqueous phase was extracted twice with ether. Theaqueous phase was acidified with 1 N aqueous HCl and extracted withether, the organic phase was dried over magnesium sulfate, and thesolvent was distilled off. 6.5 g (71%) of a yellowish oil were isolatedand were immediately reacted further.

Example 7

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionicAcid (I-116)

1.8 g (3.8 mmol) of2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionicacid were introduced into 20 ml of DMF, and 554 mg of NaH (50%suspension) were added. After the mixture had stirred for 15 minutes,855 mg (4.2 mmol) of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine wereadded, and the mixture was stirred at room temperature for 3 hours.Water was added to the mixture, which was then extracted with ether. Theaqueous phase was acidified with 1 N aqueous HCl, extracted with etherand dried over magnesium sulfate. The solvent was distilled off and 540mg (23%) of colorless powder were isolated after recrystallization fromether/n-hexane.

¹H-NMR (200 MHz): 7.0-7.4 ppm (10H, m), 6.8 (2H, d), 6.2 (1H, s), 6.15(1H, s), 3.9 (3H, s), 3.8 (3H, s), 3.7 (1H, m), 3.5 (1H, m), 2.9 (2H,tr), 2.6 (4H, m), 2.3 (3H, s), 1.2 (6H, m). EI-MS: M⁺=600.

Example 8

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-phenyl-(2E)-propenoxy)-3,3-diphenylpropionicAcid (I-27)

1.12 g (3 mmol) of2-hydroxy-3-(3-phenyl-(2E)-propenoxy)-3,3-diphenylpropionic acid wereadded to a suspension of 432 mg (9 mmol, 50%) of NaH in 20 ml of DMF,and the mixture was stirred at room temperature for 10 minutes. 614 mg(3.3 mmol) of 4,6-dimethyl-1-methylsulfonylpyrimidine were added, andthe mixture was stirred for 16 hours, then diluted with 200 ml of water,acidified with 1 N hydrochloric acid and extracted with ether. The etherphase was extracted with 1 N sodium hydroxide solution, the aqueousphase was again acidified, and the product was extracted with ether. Theorganic phase was dried over magnesium sulfate and filtered, and thesolvent was distilled off. The residue was recrystallized fromether/hexane, and 927 mg (65%) of crystalline product were isolated.

Melting point: 128-133° C.; ¹H-NMR (200 MHz): 7.3 ppm (15H, m), 6.74(1H, s), 6.7 (1H, d), 6.3 (1H, s), 6.2 (1H, dtr, 4.3 (1H, dd), 4.1 (1H,dd), 2.3 (6H, s). EI-MS: M⁺=480.

Example 9

4,6-Dimethyl-1-methylthiopyrimidine

15 g (107 mmol) of 4,6-dimethyl-1-mercaptopyrimidine and 5.14 g of NaOHwere dissolved in 175 ml of water. 12 ml (128 mmol) of dimethyl sulfatewere added dropwise to this mixture at room temperature over the courseof 10 minutes. After 1 hour, the aqueous phase was extracted 3 timeswith ether and dried over magnesium sulfate, and the solvent wasdistilled off. 15.9 g (97%) of crude product were isolated. ¹H-NMR (270MHz): 6.7 ppm (1H, s), 2.5 (3H, s), 2.3 (6H, s).

Example 10

4,6-Dimethyl-1-methylsulfonylpyrimidine

15.9 g (103 mmol) of 4,6-dimethyl-1-methylthiopyrimidine were introducedinto 120 ml of dichloromethane and 110 ml of water. Chlorine gas waspassed into saturation (yellow coloration) at 0° C. After the conversionwas complete, excess chlorine was driven out with nitrogen, the aqueousphase was extracted with dichloromethane, and the collected organicphases were dried over magnesium sulfate. The solution was concentrated,and the product (14 g, 73%) was crystallized by adding ether.

Melting point: 79-80° C. ¹H-NMR (270 MHz): 7.2 ppm (1H, s), 3.4 (3H, s),2.6 (6H, s).

Example 11

Methyl (S)-2-Hydroxy-3-methoxy-3,3-diphenylpropionate

54.4 g (200 mmol) of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acidwere introduced with 10.8 g (200 mmol) of sodium methoxide into 300 mlof DMF. 21 ml (210 mmol) of dimethylsulfate were added dropwise to thissuspension over 15 minutes, during which the temperature rises to 50° C.and the suspension becomes mobile. The mixture was stirred overnight andthen added to 1.5 l of water and ice. The aqueous phase was extractedtwice with 500 ml of ether, and the ether phase was in turn washed with200 ml of water twice. The organic phase was dried over magnesiumsulfate, the desiccant was filtered off, and the solvent was distilledoff. 55.8 g of an oil were isolated and were immediately processedfurther.

Example 12

Methyl(S)-2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate

Variant A:

27.9 g of methyl (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate (100mmol) were mixed with 1 g of p-toluenesulfonic acid and 18.2 g of2-(3,4-dimethoxyphenyl)ethanol (100 mmol) in a flask and heated to 60°C. The pressure in the flask is reduced in order to distill out themethanol which is produced, and the mixture is stirred at 60° C. for afurther 5 hours. For workup, the mixture is cooled and diluted with 300ml of ether, and the organic phase is washed first with sodiumbicarbonate solution and then several times with water. It is then driedwith magnesium sulfate, and the desiccant is filtered off and thesolvent is distilled off. A residue of 43 g of oil was isolated andcould be employed immediately for the subsequent synthesis.

Variant B:

27.9 g of methyl (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate (100mmol), 1 g of p-toluenesulfonic acid and 18.2 g (100 mmol) of2-(3,4-dimethoxyphenyl)ethanol were dissolved in 75 ml ofdichloromethane in a flask. The solution was heated and thedichloromethane was distilled out while simultaneously addingdichloromethane dropwise, in order to distill out the methanol which wasproduced, and the mixture was stirred at 60° C. for a further 5 hours.For workup, the mixture is cooled and diluted with 300 ml of ether, andthe organic phase is washed first with sodium bicarbonate solution andthen several times with water. It is then dried with magnesium sulfate,and the desiccant is filtered off and the solvent is distilled off. Aresidue of 43 g of oil was isolated and could be used immediately in thesubsequent synthesis.

Example 13

(S)-2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionicAcid

255 ml of 1 N sodium hydroxide solution were added to a solution of 74 g(170 mmol) of methyl(S)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy-3,3-diphenylpropionate in510 ml of dioxane, and the suspension was stirred at 50° C. for twohours. The mixture was diluted with 2.5 l of water and neutralized withcitric acid. The aqueous phase was extracted twice with 500 ml of ether.The organic phase was then washed with water, dried over magnesiumsulfate and filtered, and then the ether was distilled off. The residuewas purified by crystallization from ether/n-hexane, and 70 g ofcrystals were isolated.

¹H-NMR (200 MHz): 7.3 ppm (10H, m), 6.8 (1H, dbr), 6.7 (1H, dbr), 6.6(1H, sbr), 5.0 (1H, s), 3.9 (3H, s), 3.85 (3H, s), 3.6 (1H, dt), 3.4(1H, OH), 3.2 (1H, dt), 2.8 (2H, t). [α]²⁰=8.3 (1; ethanol).

Example 14

2-(4,6-(Dimethylpyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy-3,3-diphenylpropionicAcid (I-445) and

(S)-2-(4,6-Dimethylpyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-445 (S) Enantiomer) 55 g (130 mmol) of2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy-3,3-diphenylpropionic acid,dissolved in 150 ml of DMF, were added over the course of 15 minutes to9 g (390 mmol) of lithium amide in 35 ml of DMF. 25 g (137 mmol) of2-methylsulfone-4,6-dimethylpyrimidine [sic], dissolved in 75 ml of DMF,were slowly added dropwise to this, and the mixture was stirred at roomtemperature for 18 hours. For workup, the mixture was added to 2 l ofice-water and citric acid for neutralization. The crystals whichseparated out were filtered off with suction and washed with water. Themoist crystals were dissolved in dichloromethane, the solution was driedover magnesium sulfate and filtered, and the solvent was distilled off.The oily residue was taken up in ether and extracted with 130 ml of 1 Nsodium hydroxide solution, and the aqueous phase was neutralized with130 ml of 1 N hydrochloric acid, whereupon crystals separated out. 64 gof product were isolated after drying.

¹H-NMR (200 MHz): 7.3 ppm (10H, m), 6.7 (4H, m), 6.3 (1H, s), 3.9 (3H,s), 3.85 (3H, s), 3.7 (1H, dt), 3.6 (1H, dt), 2.8 (2H, t), 2.3 (6H, s).

Melting point: 125-130° C. decomposition EI-MS: M⁺=528.

(S)-2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy-3,3-diphenylpropionicacid was prepared in a similar way from(S)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionicacid and 2-methylsulfone-4,6-dimethylpyrimidine [sic] in the presence oflithium amide. [α]²⁰=111 (1; ethanol).

Example 15

The following compounds were prepared as in Example 8

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionicAcid (I-147)

Melting point: 150-155° C. EI-MS: M⁺=570.

2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionicAcid (I-651)

Melting point: 150-152° C. EI-MS: M⁺=546.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionicAcid (I-713)

Melting point: 108° C. Decomposition EI-MS: M⁺=502.

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionicAcid

Melting point: 165-167° C. EI-MS: M⁺=534.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionicAcid (I-746)

Melting point: 93-98° C. EI-MS: M⁺=518.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionicAcid (I-148)

Melting point: 130-133° C. EI-MS: M⁺=554.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionicAcid (I-710)

Melting point: 90-100° C. EI-MS: M⁺=566.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3,3-diphenylpropoxy)-3,3-di(4-chlorophenyl)propionicAcid

¹H-NMR(200 MHz): 7.3 ppm (18H, m), 6.25 (1H, s), 6.0 (1H, s), 4.0 (1H,tr), 3.8 (3H, s), 3.4 (2H, m), 2.2 (5H, m). EI-MS: M⁺=642.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionicAcid (I-699)

Melting point: 100-110° C. EI-MS: M⁺=612.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(2-methoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionicAcid (I-487)

Melting point: 85-90° C. EI-MS: M⁺=582.

2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(3-methoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionicAcid (I-486)

Melting point: 190-195° C. EI-MS: M⁺=610.

2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-phenylethylthio)-3,3-di(4-chlorophenyl)propionicAcid

Melting point: 173-175° C. ¹H-NMR (200): 7.0-7.4 ppm (13H, m), 6.0 (1H,s), 4.7 (2H, tr), 3.8 (3H, s), 3.1 (2H, tr), 2.5 (4H, m).

2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionicAcid (I-635)

Melting point: 100-110° C. EI-MS: M⁺=640.

2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(3,5-dimethoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionicAcid (1-593)

Melting point: 90-100° C. EI-MS: M⁺=640.

2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(2-methoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionicAcid (I-164)

Melting point: 135-145° C. EI-MS: M⁺=610.

2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(3,3-diphenylpropoxy)-3,3-di(4-chlorophenyl)propionicAcid

Melting point: 125-127° C. EI-MS: M⁺=670.

2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-(3,3-diphenylpropoxy)-3,3-di(4-chlorophenyl)propionicAcid

Melting point: 135-140° C. EI-MS: M⁺=668.

2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-(2-phenylethylthio)-3,3-di(4-chlorophenyl)propionicAcid

Melting point: 135-140° C. ¹H-NMR (200): 7.0-7.5 ppm (13H, m), 5.9 (1H,s), 3.9 (3H, s), 2.6-2.8 (8H, m), 2.1 (2H, m).

2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-(2-(2-methoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionicAcid

Melting point: 105-115° C. EI-MS: M⁺=608.

2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-(2-(3-methoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionicAcid

Melting point: 110-120° C. EI-MS: M⁺=608.

2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-(2-(4-dimethylaminophenyl)ethoxy)-3,3-di(4-chlorophenyl)propionicAcid

Melting point: 135-140° C. EI-MS: M⁺=621.

2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionicAcid

Melting point: 125-130° C. EI-MS: M⁺=638.

2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3-(2-(3,5-dimethoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)propionicAcid

Melting point: 125-130° C. EI-MS: M⁺=638.

2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-370)

Melting point: 128-130° C. EI-MS: M⁺=526.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-phenylethoxy)-3,3-diphenylpropionicAcid (I-719)

Melting point: 155° C. Decomposition EI-MS: M⁺=484.

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-(2-phenylethoxy)-3,3-diphenylpropionicAcid

Melting point: 203° C. Decomposition EI-MS: M⁺=500.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-phenylethoxy)-3,3-diphenylpropionic Acid (I-720)

Melting point: 130-133° C. EI-MS: M⁺=468.

2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-phenylethoxy)-3,3-diphenylpropionicAcid (I-657)

Melting point: 138-142° C. EI-MS: M⁺=512.

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-diphenylpropionicAcid

Melting point: 155-158° C. EI-MS: M⁺=514.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-465)

Melting point: 145-147° C. EI-MS: M⁺=498.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3-(4-methoxyphenyl)propoxy)-3,3-diphenylpropionicAcid (I-554)

Melting point: 160-165° C. EI-MS: M⁺=528.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(4-methoxyphenyl)propoxy)-3,3-diphenylpropionicAcid (I-555)

Melting point: 165-170° C. EI-MS: M⁺=512.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3-(3,4,5-trimethoxyphenyl)propoxy)-3,3-diphenylpropionicAcid (I-335)

¹H-NMR (200): 7.2-7.4 ppm (10H, m), 6.3 (2H, s), 6.2 (2H, s), 3.8 (3H,s), 3.75 (10H, s), 3.4 (2H, m), 2.6 (2H, m), 2.25 (3H, s), 1.9 (2H, m).EI-MS: M⁺=588.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(3,4,5-trimethoxyphenyl)propoxy)-3,3-diphenylpropionicAcid (I-336)

¹H-NMR (200): 7.2-7.5 ppm (10H, m), 6.6 (1H, s), 6.3 (3H, S), 3.8 (9H,s), 3.4 (2H, m), 2.6 (2H, m), 2.3 (6H, s), 1.9 (2H, m). EI-MS: M⁺=572.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3-(2-chlorophenyl)propoxy)-3,3-diphenylpropionicAcid (I-383)

¹H-NMR (200): 7.1-7.5 ppm (14H, m), 6.24 (1H, s), 6.23 (1H, s), 3.8 (3H,s), 3.4 (2H, m), 2.75 (2H, m), 2.25 (3H, s), 1.9 (2H, m). EI-MS: M⁺=532.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(2-chlorophenyl)propoxy)-3,3-diphenylpropionicAcid (I-384)

Melting point: 172-178° C. EI-MS: M⁺=516.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(4-chlorophenyl)propoxy)-3,3-diphenylpropionicAcid (I-251)

¹H-NMR (200): 7.0-7.4 ppm (14H, m), 6.6 (1H, s), 6.3 (1H, s), 3.5 (2H,m), 2.7 (2H, m), 2.3 (6H, s), 1.9 (2H, m). EI-MS: M⁺=516.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(3,4-dimethoxyphenyl)propoxy)-3,3-diphenylpropionicAcid (I-490))

¹H-NMR (200): 7.1-7.5 ppm (10H, m), 6.74 (1H, s), 6.7 (3H, S), 6.3 (1H,s), 3.8 (6H, s), 3.5 (2H, m), 2.7 (2H, m), 2.3 (6H, s), 1.9 (2H, m).EI-MS: M⁺=542.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-propoxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-69)

Melting point: 115-119° C. EI-MS: M⁺=542.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-butoxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-71)

Melting point: 118-122° C. EI-MS: M⁺=556.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-butoxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-70)

Melting point: 122-125° C. EI-MS: M⁺=540.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3-phenyl-(2E)-propenoxy)-3,3-diphenylpropionicAcid (I-44)

Melting point: 171-174° C. EI-MS: M⁺=496.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3-(2-methylphenyl)propoxy)-3,3-diphenylpropionicAcid (I-107)

Decomposition: 144-146° C. EI-MS: M⁺=512.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(2-methylphenyl)propoxy)-3,3-diphenylpropionicAcid (I-90)

Decomposition: 173-176° C. EI-MS: M⁺=496.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3-(4-methylphenyl)propoxy)-3,3-diphenylpropionicAcid (1-363)

Decomposition: 158-161° C. EI-MS: M⁺=512.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-(4-methylphenyl)propoxy)-3,3-diphenylpropionicAcid (I-346)

Decomposition: 163-167° C. EI-MS: M⁺=496.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-methylthiophenyl)ethoxy)-3,3-diphenylpropionicAcid (I-246)

Decomposition: 136-138° C. EI-MS: M⁺=530.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-methylthiophenyl)ethoxy)-3,3-diphenylpropionicAcid (I-217)

Decomposition: 166-169° C. EI-MS: M⁺=514.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-ethoxy-3-methoxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (1-145)

Decomposition: 141-145° C. EI-MS: M⁺=558.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-ethoxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-510)

Decomposition: 131-135° C. EI-MS: M⁺=528.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-i-propylphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-705)

¹H-NMR (200 MHz, DMSO): 7.0-7.35 ppm (14H, m), 6.35 (1H, s), 6.1 (1H,s), 4.0 (1H, m), 3.9 (3H, s), 3.8 (3H, s), 3.7 (1H, m), 2.9 (3H, m), 2.2(3H, s), 1.1 (6H, d). EI-MS: M⁺=526.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(3,4-methylenedioxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (1-568)

Decomposition: 146-148° C. EI-MS: M⁺=528.

2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(3,4-methylenedioxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-501)

Decomposition: 145-149° C. EI-MS: M⁺=556.

2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(4-ethoxy-3-methoxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-735)

¹H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (10H, m), 6.85 (2H, m), 6.7 (1H, d),6.1 (1H, s), 4.6 (2H, tr), 4.0 (3H, m), 3.85 (3H, s), 3.75 (3H, s), 3.65(1H, m), 3.05 (2H, tr), 2.8 (2H, m), 1.25 (3H, m). EI-MS: M⁺=586.

2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(4-ethoxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-407)

¹H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (12H, m), 6.8 (2H, d), 6.1 (1H, s),4.65 (2H, tr), 3.95 (3H, m), 3.8 (3H, s), 3.65 (1H, m), 3.05 (2H, tr),2.8 (2H, m), 1.25 (3H, m). EI-MS: M⁺=556.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-ethoxy-3-methoxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (1-146)

Decomposition: 129-134° C. EI-MS: M⁺=542.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(3,4-methylenedioxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-569)

¹H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (10H, m), 6.9 (1H, s), 6.8 (2H, m),6.7 (1H, d), 6.2 (1H, s), 6.0 (2H, s), 3.95 (3H, m), 3.65 (1H, m), 2.8(2H, m), 2.3 (6H, s). EI-MS: M⁺=512.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-ethoxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-473)

Decomposition: 145-148° C. EI-MS: M⁺=512.

2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(4-i-propylphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-604)

¹H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (14H, m), 6.1 (1H, s), 4.6 (2H, tr),3.9 (1H, m), 3.8 (3H, s), 3.6 (1H, m), 3.0 (2H, tr), 2.8 (3H, m), 1.1(6H, d). EI-MS: M⁺=554.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-i-propylphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-672)

Decomposition: 156-160° C. EI-MS: M⁺=510.

2-(4-Methoxy-5,6-dihydrofuro(2,3d)-2-pyrimidinyloxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-di(4-methylphenyl)propionicAcid (I-517)

¹H-NMR (200 MHz, DMSO): 7.0-7.3 ppm (10H, m), 6.8 (2H, d), 6.0 (1H, s),4.6 (2H, tr), 3.85 (3H, s), 3.8 (1H, m), 3.7 (3H, s), 3.6 (1H, m), 3.0(2H, tr), 2.8 (2H, tr), 1.1 (6H, d). EI-MS: M⁺=570.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-622)

¹H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (12H, m), 6.8 (2H, d), 6.4 (1H, s),6.1 (1H, s), 4.0 (1H, m), 3.7 (3H, s), 3.7 (1H, m), 2.8 (2H, tr), 2.3(3H, s). EI-MS: M⁺=514.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-diphenylpropionicAcid (I-585)

¹H-NMR (200 MHz, DMSO): 7.1-7.4 ppm (12H, m), 6.8 (3H, m), 6.1 (1H, s),4.0 (1H, m), 3.7 (3H, s), 3.6 (1H, m), 2.8 (2H, r), 2.3 (6H, s). EI-MS:M⁺=498.

2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(3-phenylpropoxy)-3,3-diphenylpropionicAcid (I-499)

Decomposition: 153-155° C. EI-MS: M⁺=498.

2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(3-phenylpropoxy)-3,3-diphenylpropionicAcid (I-500)

Decomposition: 148-151° C. EI-MS: M⁺=482.

The compounds listed in Table 1 can be prepared in a similar way or asdescribed in the general part.

TABLE I [sic] I

No. R¹ R⁴, R⁵ Q R⁶ R² R³ Z X Y W I-1 COOH phenyl —CH₂—CH₂— phenyl OMe MeCH N N S I-2 COOMe phenyl —CH₂—CH₂— phenyl CF₃ Me CH N N O I-3 COOH4-Br-phenyl —CH₂—CH₂— phenyl OMe OMe CH N N O I-4 COOH phenyl—CH₂—C(CH₃)₂— phenyl OMe Me CH N N O I-5 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂—3,4-di-OMe-phenyl Me Me CH N N O I-6 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂—3,4-di-OMe-phenyl Me Me N N N O I-7 COOH phenyl —CH₂—CH₂—3,4-di-Cl-phenyl Me Me CH N N O I-8 COOH phenyl —CH₂—CH₂— phenyl Me Me NN CH O I-9 COOH phenyl —CH₂—CH₂— phenyl ethyl Me N N N O I-10 COOHphenyl —CH═CH—CH₂— phenyl ethyl Me CH N N O I-11 COOH phenyl —CH═CH—CH₂—phenyl OMe CH₂—CH₂—CH₂—C N N O I-12 COOH phenyl —CH═CH—CH₂— phenyl OMeO—CH₂—CH₂—C N N O I-13 COOH phenyl —CH₂—CH₂— phenyl OMe CH₂—CH₂—CH₂—C NN S I-14 COOEt phenyl —CH₂—CH₂— phenyl OMe O—CH₂—CH₂—C N N O I-15 COOH4-Et-phenyl —CH₂—CH₂— 4-SMe-phenyl Me Me CH N N O I-16 COOH 4-Et-phenyl—CH₂—CH₂— 4-SMe-phenyl Me Me N N N O I-17 COOMe phenyl —CH₂—CH₂—4-OMe-phenyl OMe Me CH N N O I-18 COOEt phenyl —CH₂—CH₂— 4-OMe-phenyl MeMe CH N N S I-19 tetrazole phenyl —CH₂—CH₂— 4-OMe-phenyl OMe O—CH₂—CH₂—CN N O [sic] I-20 COOH phenyl —C(CH₃)₂—CH₂— 4-OMe-phenyl OMe O—CH₂—CH₂—CN N O I-21 COOH phenyl —CH₂—C(CH₃)₂— 4-OMe-phenyl OMe O—CH₂—CH₂—C N N OI-22 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂— 4-OMe-phenyl OMe O—CH₂—CH₂—C N N OI-23 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl OMe Me CH N N OI-24 COOH 4-Br-phenyl —CH₂—CH₂— 4-OMe-phenyl OMe OMe CH N N O I-25 COOHphenyl —CH₂—CH₂— 4-OMe-phenyl OMe Me N N N O I-26 COOH phenyl —CH₂—CH₂—4-OMe-phenyl Me Me N N CH O I-27 COOH phenyl —CH═CH—CH₂— phenyl Me Me CHN N O I-28 COOH phenyl —CH═CH—CH₂— phenyl Me Me N N N O I-29 COOH phenyl—CH₂—CH₂— 4-OMe-phenyl ethyl Me N N N O I-30 COOH phenyl —CH₂—CH₂—4-OMe-phenyl OMe CH₂—CH₂—CH₂—C N N S I-31 COOH 4-Et-phenyl —CH₂—CH₂—3-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-32 COOH 4-Et-phenyl —CH₂—CH₂—4-SMe-phenyl OMe Me CH N N O I-33 COOEt phenyl —CH₂—CH₂— 4-OMe-phenylOMe O—CH₂—CH₂—C N N O I-34 COOH phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl OMeO—CH₂—CH₂—C N N S I-35 COOMe phenyl —C(CH₃)₂—CH₂— 3,4-di-OMe-phenyl OMeMe N N CH S I-36 COOH phenyl —C(CH₃)₂—CH₂— 3,4-di-OMe-phenyl ethyl Me CHN N O I-37 COOH 4-Br-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl CF₃ Me CH N N OI-38 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂— 4-OMe-phenyl Me Me N N N O I-39 COOH4-Cl-phenyl —CH₂—CH₂—CH₂— 4-OMe-phenyl ethyl Me CH N N O I-40 COOHphenyl —CH₂—CH₂— 3,4-di-Me-phenyl OMe Me CH N N O I-41 COOH phenyl—CH₂—CH₂— 3,4-di-OMe-phenyl SMe Me CH N N O I-42 COOH phenyl —CH₂—CH₂—3,4-di-OMe-phenyl Me Me N N CH O I-43 COOH phenyl —CH═CH—CH₂— phenyl CF₃Me CH N N O I-44 COOH phenyl —CH═CH—CH₂— phenyl OMe Me CH N N O I-45COOH phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl ethyl Me CH N N S I-46 COOBzlphenyl —CH₂—CH₂— 3,4-di-OMe-phenyl OMe CH₂—CH₂—CH₂—C N N O I-47 COOH4-Et-phenyl —CH₂—CH₂— 3-OMe-phenyl Me Me N N N O I-48 COOH 4-Et-phenyl—CH₂—CH₂— 3-OMe-phenyl ethyl Me CH N N O I-49 COOH 4-F-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-50 COOH phenyl —C(CH₃)₂—CH₂—3,4,5-tri-OMe-phenyl CF₃ Me CH N N O I-51 COOH phenyl —CH₂—CH₂—3-Me-4-Et-phenyl OMe CF₃ CH N N O I-52 COOH phenyl —CH₂—CH₂—3-Me-4-Et-phenyl OMe Me CH N N O I-53 COOH 4-F-phenyl —CH₂—CH₂—4-Br-phenyl Me Me N N N O I-54 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂—4-OMe-phenyl OMe Me CH N N O I-55 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂—4-OMe-phenyl Me Me CH N N O I-56 COOH phenyl —CH₂—CH₂— 4-Br-phenyl Me MeN N CH O I-57 COOH phenyl —CH₂—CH₂— 3-Br-phenyl ethyl Me CH N N S I-58COOH phenyl —CH₂—CH₂— 2-Me-phenyl OMe CH₂—CH₂—CH₂—C N N O I-59 COOHphenyl —CH═CH—CH₂— 4-Me-phenyl OMe CH₂—CH₂—CH₂—C N N O I-60 COOH phenyl—CH═CH—CH₂— 4-Me-phenyl OMe O—CH₂—CH₂—C N N O I-61 COOH 4-F-phenyl—CH₂—CH₂— 3-Me-phenyl OMe O—CH₂—CH₂—C N N O I-62 COOH phenyl —CH₂—CH₂—3-Me-4-SMe-phenyl CF₃ Me CH N N O I-63 COOH 4-Et-phenyl —CH₂—CH₂—3-OMe-phenyl OMe Me CH N N O I-64 COOH 4-Et-phenyl —CH₂—CH₂—3-OMe-phenyl Me Me CH N N O I-65 tetrazole phenyl —CH₂—CH₂— 4-SMe-phenylMe OMe CH N N O [sic] I-66 COOH 3-OMe-phenyl —CH₂—CH₂— 4-SMe-phenyl OMeMe CH N N O I-67 COOH phenyl —O—CH₂—CH₂— 4-SMe-phenyl Me Me CH N N OI-68 COOH phenyl —CH₂—CH₂— 4-n-propoxy-phenyl Me Me CH N N O I-69 COOHphenyl —CH₂—CH₂— 4-n-propoxy-phenyl OMe Me CH N N O I-70 COOH phenyl—CH₂—CH₂— 4-n-butoxy-phenyl Me Me CH N N O I-71 COOH phenyl —CH₂—CH₂—4-n-butoxy-phenyl OMe Me CH N N O I-72 COOH phenyl —O—CH₂—CH₂—4-SMe-phenyl Me Me CH N CH O I-73 COOH phenyl —O—CH₂—CH₂— 4-SMe-phenylethyl Me CH N N S I-74 COOH phenyl —CH₂—CH₂—CH₂— 2-Me-phenyl ethyl Me CHN N O I-75 COOH phenyl —CH₂—CH₂—CH₂— 2-Me-phenyl OMe CH₂—CH₂—CH₂—C N N OI-76 COOH phenyl —CH₂—CH₂— 2-Me-4-SMe-phenyl OMe CH₂—CH₂—CH₂—C N N OI-77 COOH phenyl —C(CH₃)₂—CH₂— 4-SMe-phenyl OMe O—CH₂—CH₂—C N N O I-78COOMe phenyl —CH₂—CH₂— 4-OEt-3-OMe-phenyl CF₃ Me CH N N O I-79 COOHphenyl —CH═CH—CH₂— 4-Me-phenyl Me Me N N N O I-80 COOH phenyl—CH═CH—CH₂— 4-Me-phenyl ethyl Me CH N N O I-81 COOH phenyl —CH₂—CH₂—4-(di-Me-amino)-phenyl OMe O—CH₂—CH₂—C N N O I-82 COOH 4-Cl-phenyl—CH₂—CH₂— 4-OMe-phenyl OMe Me CH N N O I-83 COOH 4-Et-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl ethyl Me CH N N O I-84 COOH 4-Et-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-85 COOH 3-OMe-phenyl —CH₂—CH₂—4-OEt-3-OMe-phenyl OMe Me CH N N O I-86 COOH phenyl —O—CH₂—CH₂—4-OEt-3-OMe-phenyl Me Me CH N N O I-87 COOH phenyl —S—CH₂—CH₂—3-OMe-4-Cl-phenyl Me Me CH N N O I-88 COOH phenyl —CH₂—CH₂—3-OMe-4-Cl-phenyl ethyl Me CH N N O I-89 COOH 3-Me-phenyl —CH₂—CH₂—3-OMe-4-Cl-phenyl OMe CH₂—CH₂—CH₂—C N N O I-90 COOH phenyl —CH₂—CH₂—CH₂—2-Me-phenyl Me Me CH N N O I-91 COOH phenyl —CH₂—CH₂—CH₂— 2-Me-phenyl MeMe N N N O I-92 COOH phenyl —CH₂—CH₂— 4-OEt-3-OMe-phenyl OMe O—CH₂—CH₂—CN N S I-93 COOMe phenyl —CH₂—CH₂— 4-iPr-phenyl CF₃ Me CH N N O I-94 COOH2-Me-phenyl —CH₂—CH₂— 4-F-phenyl OMe Me CH N N O I-95 COOH phenyl—CH═CH—CH₂— 4-Me-phenyl OMe Me CH N N O I-96 COOH phenyl —CH═CH—CH₂—4-Me-phenyl Me Me CH N N O I-97 COOH 2-Me-phenyl —CH₂—CH₂— 4-iPr-phenylMe Me CH N N O I-98 COOH phenyl —O—CH₂—CH₂— phenyl Me Me N N N O I-99COOH 4-Et-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl Me Me CH N N O I-100 COOH4-Et-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl Me Me N N N O I-101 COOH phenyl—CH₂—CH₂— 4-(di-Me-amino)-phenyl Me Me N N N O I-102 COOH phenyl—CH₂—CH₂— 4-(di-Me-amino)-phenyl ethyl Me CH N N O I-103 COOH2-Me-phenyl —CH₂—CH₂— 4-Cl-phenyl ethyl Me CH N N O I-104 COOH4-F-phenyl —CH₂—CH₂— 4-OMe-phenyl OMe CH₂—CH₂—CH₂—C N N O I-105 COOHphenyl —C(CH₃)₂—CH₂— 3-Cl-phenyl OMe O—CH₂—CH₂—C N N O I-106 COOH phenyl—CH₂—CH₂—CH₂— 2-Me-phenyl CF₃ Me CH N N O I-107 COOH phenyl—CH₂—CH₂—CH₂— 2-Me-phenyl OMe Me CH N N O I-108 COOH phenyl —CH₂—CH₂—3,4-methylenedioxyphenyl Me Me N N CH O I-109 COOMe phenyl —CH₂—CH₂—3,4-methylenedioxyphenyl OMe Me CH N N O I-110 COOH phenyl —CH₂—CH₂—3,4-methylenedioxyphenyl Me Me CH N N S I-111 COOH phenyl —CH═CH—CH₂—4-iPr-phenyl OMe O—CH₂—CH₂—C N N O I-112 COOH phenyl —CH═CH—CH₂—4-Me-phenyl CF₃ Me CH N N O I-113 COOH phenyl —CH₂—CH₂— 3,4-di-Me-phenylMe Me CH N N O I-114 COOH phenyl —O—CH₂—CH₂— 3,4-di-Me-phenyl ethyl MeCH N N O I-115 COOH 4-Et-phenyl —CH₂—CH₂— 4-OMe-phenyl OMe O—CH₂—CH₂—C NN O I-116 COOH 4-Et-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl OMe Me CH N N OI-117 COO- phenyl —CH₂—CH₂— 3,4-methylenedioxyphenyl OMe CH₂—CH₂—CH₂—C NN O i-Propyl I-118 COOH phenyl —CH₂—CH₂— 3,4-di-Me-phenyl OMeO—CH₂—CH₂—C N N O I-119 COOH phenyl —CH₂—CH₂— 4-(di-Me-amino)-phenyl OMeMe CH N N O I-120 COOH phenyl —CH₂—CH₂— 4-(di-Me-amino)-phenyl Me Me CHN N O I-121 COOH 4-F-phenyl —CH₂—CH₂— 4-Me-phenyl CF₃ Me CH N N O I-122COOH phenyl —CH₂—CH₂—CH₂— 3-OMe-phenyl ethyl Me CH N N O I-123 COOHphenyl —CH₂—CH₂—CH₂— 3-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-124 COOHphenyl —S—CH₂—CH₂— 4-Me-phenyl OMe Me CH N N O I-125 COOH phenyl—CH(OH)—CH₂— 4-Me-phenyl Me Me CH N N O I-126 COOH phenyl —CH₂—CH₂—3-OMe-4-Me-phenyl Me Me CH N N O I-127 COOH phenyl —CH═CH—CH₂—4-iPr-phenyl ethyl Me CH N N O I-128 COOH phenyl —CH═CH—CH₂—4-iPr-phenyl OMe Me CH N N O I-129 COOH phenyl —CH₂—CH₂— 4-Me-phenylethyl Me N N CH O I-130 COOH phenyl —CH₂—CH₂— 3-OMe-4-Me-phenyl OMeCH₂—CH₂—CH₂—C N N O I-131 COOH 4-Et-phenyl —CH₂—CH₂— 4-OMe-phenyl Me MeN N N O I-132 COOH 4-Et-phenyl —CH₂—CH₂— 4-OMe-phenyl ethyl Me CH N N OI-133 COOH phenyl —CH₂—CH₂— 4-Me-phenyl OMe O—CH₂—CH₂—C N N S I-134COOButyl phenyl —CH₂—CH₂— 4-Et-phenyl CF₃ Me CH N N O I-135 COOH4-I-phenyl —CH₂—CH₂— 4-Et-phenyl OMe Me CH N N O I-136 COOH phenyl—CH(OH)—CH₂— 4-Et-phenyl Me Me CH N N O I-137 COOH phenyl —CH₂—CH₂—2-OMe-phenyl OMe CH₂—CH₂—CH₂—C N N O I-138 COOH phenyl —CH₂—CH₂—CH₂—3-OMe-phenyl Me Me CH N N O I-139 COOH phenyl —CH₂—CH₂—CH₂— 3-OMe-phenylMe Me N N N O I-140 COOH phenyl —CH₂—CH₂— 2-OMe-phenyl OMe O—CH₂—CH₂—C NN O I-141 COOH phenyl —CH₂—CH₂— 3-OMe-4-Et-phenyl Me Me N N N O I-142COOH phenyl —CH₂—CH₂— 4-Et-phenyl ethyl Me N N N O I-143 COOH phenyl—CH═CH—CH₂— 4-Cl-phenyl ethyl Me CH N N O I-144 COOH phenyl —CH═CH—CH₂—4-Cl-phenyl OMe CH₂—CH₂—CH₂—C N N O I-145 COOH phenyl —CH₂—CH₂—4-OEt-3-OMe-phenyl OMe Me CH N N O I-146 COOH phenyl —CH₂—CH₂—4-OEt-3-OMe-phenyl Me Me CH N N O I-147 COOH 4-Et-phenyl —CH₂—CH₂—4-OMe-phenyl OMe Me CH N N O I-148 COOH 4-Et-phenyl —CH₂—CH₂—4-OMe-phenyl Me Me CH N N O I-149 COOH phenyl —CH₂—CH₂—3-OMe-4-Et-phenyl OMe O—CH═CH—C N N O I-150 COOH phenyl —CH₂—CH₂—3-OMe-4-Et-phenyl OMe O—CH₂—CH₂—C N N O I-151 COOH 4-Me-phenyl —CH₂—CH₂—cyclohexyl CF₃ Me CH N N O I-152 COOH phenyl —CH₂—CH₂— cyclohexyl OMeethyl CH N N O I-153 COOMe phenyl —CH₂—CH₂— cyclohexyl OMe Me CH N N OI-154 COOH phenyl —CH₂—CH₂—CH₂— 3-OMe-phenyl CF₃ Me CH N N O I-155 COOHphenyl —CH₂—CH₂—CH₂— 3-OMe-phenyl OMe Me CH N N O I-156 COOH phenyl—CH₂—CH₂— cyclohexyl Me Me CH N CH O I-157 COOH phenyl —CH₂—CH₂—cyclohexyl Me Me N N CH O I-158 COOH 4-Cl-phenyl —CH₂—CH₂— cyclohexylethyl Me CH N N O I-159 COOH phenyl —CH═CH—CH₂— 4-Cl-phenyl Me Me CH N NO I-160 COOH phenyl —CH═CH—CH₂— 4-Cl-phenyl Me Me N N N O I-161 COOHphenyl —CH₂—CH₂— 2-OMe-phenyl Me Me N N N O I-162 COOH phenyl —CH₂—CH₂—2-OMe-phenyl ethyl Me CH N N O I-163 COOH 4-Cl-phenyl —CH₂—CH₂—2-OMe-phenyl ethyl Me CH N N O I-164 COOH 4-Cl-phenyl —CH₂—CH₂—2-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-165 COOH 4-Et-phenyl —CH₂—CH₂—cyclohexyl OMe CH₂—CH₂—CH₂—C N N O I-166 COOH phenyl —CH₂—CH₂—cyclohexyl OMe O—CH₂—CH₂—C N N S I-167 COOH phenyl —CH₂—CH₂—4-SMe-phenyl OMe O—CH₂—CH₂—C N N O I-168 COOH phenyl —CH₂—CH₂—4-OEt-3-OMe-phenyl CF₃ Me CH N N O I-169 COOH phenyl —CH₂—CH₂—3-Me-4-Cl-phenyl CF₃ Me CH N N O I-170 COOH phenyl —CH₂—CH₂—CH₂—4-OEt-phenyl ethyl Me CH N N O I-171 COOH phenyl —CH₂—CH₂—CH₂—4-OEt-phenyl OMe CH₂—CH₂—CH₂—C N N O I-172 COOH phenyl —CH₂—CH₂—4-Cl-phenyl OMe Me CH N N S I-173 COOH 3-Me-phenyl —CH₂—CH₂— 4-Cl-phenylMe Me CH N N O I-174 COOH phenyl —O—CH₂—CH₂— 4-Cl-phenyl ethyl Me N N NO I-175 COOH phenyl —CH═CH—CH₂— 4-Cl-phenyl CF₃ Me CH N N O I-176 COOHphenyl —CH═CH—CH₂— 4-Cl-phenyl OMe Me CH N N O I-177 COOH phenyl—CH₂—CH₂— 2-Me-4-Cl-phenyl SMe Me CH N N O I-178 COOH phenyl —CH₂—CH₂—cyclohexyl OMe CH₂—CH₂—CH₂—C N N O I-179 COOH 4-CF₃-phenyl —CH₂—CH₂—3-OMe-phenyl Me Me CH N N O I-180 COOH 4-CF₃-phenyl —CH₂—CH₂—3-OMe-phenyl Me Me N N N O I-181 COOH phenyl —CH₂—CH₂— cyclohexyl OMeO—CH₂—CH₂—C N N O I-182 COOBzl phenyl —CH₂—CH₂— 4-Cl-phenyl OMeCH₂—CH₂—CH₂—C N N O I-183 COOH phenyl —CH₂—CH₂— 2-Me-4-Cl-phenyl OMeO—CH₂—CH₂—C N N O I-184 COOH phenyl —CH(OH)—CH₂— naphth-2-yl CF₃ Me CH NN O I-185 COOH phenyl —CH₂—CH₂— 2-OMe-phenyl OMe Me CH N N O I-186 COOHphenyl —CH₂—CH₂—CH₂— 4-OEt-phenyl Me Me CH N N O I-187 COOH phenyl—CH₂—CH₂—CH₂— 4-OEt-phenyl Me Me N N N O I-188 COOH phenyl —CH₂—CH₂—2-OMe-phenyl Me Me CH N N O I-189 COOH 2-Me-phenyl —CH₂—CH₂— naphth-2-ylOMe Me CH N N O I-190 COOH phenyl —CH₂—CH₂— naphth-2-yl Me Me CH N N SI-191 COOH phenyl —CH═CH—CH₂— 4-Cl-phenyl OMe O—CH₂—CH₂—C N N O I-192COOH phenyl —CH═CH—CH₂— 4-iPr-phenyl Me Me CH N N O I-193 COOH phenyl—CH₂—CH₂— 4-SMe-phenyl ethyl Me CH N N O I-194 COOH phenyl —CH₂—CH₂—4-SMe-phenyl OMe CH₂—CH₂—CH₂—C N N O I-195 COOH 4-CF₃-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-196 COOH 4-CF₃-phenyl—CH₂—CH₂— 3-OMe-phenyl OMe Me CH N N O I-197 COOH phenyl —CH₂—CH₂—naphth-2-yl Me Me N N CH O I-198 COOH phenyl —CH₂—CH₂— 1-Me-naphth-2-ylethyl Me CH N N O I-199 COOH phenyl —CH₂—CH₂— 1-Me-naphth-2-yl OMeCH₂—CH₂—CH₂—C N N O I-200 COOMe phenyl —CH₂—CH₂— naphth-2-yl OMeO—CH₂—CH₂—C N N O I-201 COOEt phenyl —CH₂—CH₂— 4-OEt-phenyl CF₃ Me CH NN O I-202 COOH phenyl —CH₂—CH₂—CH₂— 4-OEt-phenyl CF₃ Me CH N N O I-203COOH phenyl —CH₂—CH₂—CH₂— 4-OEt-phenyl OMe Me CH N N O I-204 COOH phenyl—CH₂—CH₂— cyclohexyl Me Me N N N O I-205 COOH phenyl —CH₂—CH₂—cyclohexyl ethyl Me CH N N O I-206 tetrazole phenyl —CH₂—CH₂—4-OEt-phenyl OMe Me CH N N O [sic] I-207 COOH phenyl —CH═CH—CH₂—3,4-di-OMe-phenyl ethyl Me CH N N O I-208 COOH phenyl —CH═CH—CH₂—3,4-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-209 COOH phenyl —CH₂—CH₂—4-OH-phenyl Me Me CH N N O I-210 COOH phenyl —CH₂—CH₂— 4-OH-phenyl ethylMe N N CH O I-211 COOH 4-CF₃-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl Me Me NN N O I-212 COOH 4-CF₃-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl ethyl Me CH NN O I-213 COOH phenyl —CH₂—CH₂— 3-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-214COOH phenyl —CH₂—CH₂— 2-OMe-phenyl CF₃ Me CH N N O I-215 COOH phenyl—CH₂—CH₂— 4-OEt-phenyl ethyl Me CH N N S I-216 COOH phenyl —C(CH₃)₂—CH₂—4-OEt-phenyl OMe CH₂—CH₂—CH₂—C N N O I-217 COOH phenyl —CH₂—CH₂—4-SMe-phenyl Me Me CH N N O I-218 COOH phenyl —CH₂—CH₂—CH₂— 4-Cl-phenylOMe CH₂—CH₂—CH₂—C N N O I-219 COOH phenyl —CH₂—CH₂—CH₂— 4-Cl-phenyl OMeO—CH₂—CH₂—C N N O I-220 COOH phenyl —CH₂—CH₂— 4-SMe-phenyl Me Me N N N OI-221 COOH phenyl —O—CH₂—CH₂— 4-OEt-phenyl OMe O—CH₂—CH₂—C N N O I-222COOH 4-Br-phenyl —CH₂—CH₂— 3,5-di-OMe-phenyl CF₃ Me N N CH O I-223 COOHphenyl —CH═CH—CH₂— 3,4-di-OMe-phenyl Me Me CH N N O I-224 COOH phenyl—CH═CH—CH₂— 3,4-di-OMe-phenyl Me Me N N N O I-225 COOH 4-I-phenyl—CH₂—CH₂— 3,5-di-OMe-phenyl OMe Me CH N N O I-226 COOH phenyl —CH₂—CH₂—3,5-di-OMe-phenyl Me Me CH N CH O I-227 COOH 4-CF₃-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl OMe Me CH N N O I-228 COOH 4-CF₃-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl Me Me CH N N O I-229 COOH phenyl —CH₂—CH₂—3,5-di-OMe-phenyl ethyl Me N N N O I-230 COOH phenyl —CH₂—CH₂—cyclohexyl OMe Me CH N N O I-231 COOH phenyl —CH₂—CH₂— cyclohexyl Me MeCH N N O I-232 COOH phenyl —CH(OH)—CH₂— 3,5-di-OMe-phenyl ethyl Me CH NN O I-233 COOH phenyl —CH₂—CH₂— 3,5-di-OMe-4-Cl-phenyl OMe CH₂—CH₂—CH₂—CN N O I-234 COOH phenyl —CH₂—CH₂—CH₂— 4-Cl-phenyl Me Me N N N O I-235COOH phenyl —CH₂—CH₂—CH₂— 4-Cl-phenyl ethyl Me CH N N O I-236 COOMephenyl —CH₂—CH₂— 3,5-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-237 COOHphenyl —CH₂—CH₂— 3-OMe-phenyl ethyl Me CH N N O I-238 COOH phenyl—CH₂—CH₂— 3-OMe-phenyl OMe CH₂—CH₂—CH₂—C N N O I-239 COOH phenyl—CH═CH—CH₂— 3,4-di-OMe-phenyl CF₃ Me CH N N O I-240 COOH phenyl—CH═CH—CH₂— 3,4-di-OMe-phenyl OMe Me CH N N O I-241 COOH phenyl—CH₂—CH₂— 2-Me-3-OMe-phenyl CF₃ Me CH N N O I-242 COOH phenyl —CH₂—CH₂—3-OMe-phenyl OMe Me N N N O I-243 COOH 4-CF₃-phenyl —CH₂—CH₂—4-OMe-phenyl ethyl Me CH N N O I-244 COOH 4-CF₃-phenyl —CH₂—CH₂—4-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-245 COOH phenyl —CH₂—CH₂—4-SMe-phenyl OMe OMe CH N N O I-246 COOH phenyl —CH₂—CH₂— 4-SMe-phenylOMe Me CH N N O I-247 COOH phenyl —CH₂—CH₂— 3-OMe-phenyl Me Me CH N CH OI-248 COOH phenyl —CH₂—CH₂— 3-OMe-phenyl Me Me N N CH O I-249 COOHphenyl —CH₂—CH₂— 3-OMe-phenyl ethyl Me CH N N S I-250 COOH phenyl—CH₂—CH₂—CH₂— 4-Cl-phenyl OMe Me CH N N O I-251 COOH phenyl—CH₂—CH₂—CH₂— 4-Cl-phenyl Me Me CH N N O I-252 COOH 4-F-phenyl —CH₂—CH₂—3-OMe-phenyl OMe CH₂—CH₂—CH₂—C N N O I-253 COOH phenyl —CH₂—CH(CH₃)—3-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-254 COOH phenyl —CH₂—CH₂—cyclohexyl CF₃ Me CH N N O I-255 COOH phenyl —CH═CH—CH₂— 4-OMe-phenylOMe CH₂—CH₂—CH₂—C N N O I-256 COOH phenyl —CH═CH—CH₂— 4-OMe-phenyl OMeO—CH₂—CH₂—C N N O I-257 COOH phenyl —CH₂—CH₂— cyclohexyl OMe OMe CH N NO I-258 tetrazole phenyl —CH₂—CH₂— 2-OMe-phenyl CF₃ Me CH N N O [sic]I-259 COOH 4-CF₃-phenyl —CH₂—CH₂— 4-OMe-phenyl Me Me CH N N O I-260 COOH4-CF₃-phenyl —CH₂—CH₂— 4-OMe-phenyl Me Me N N N O I-261 COOH phenyl—CH(2-OMe-phenyl)-CH₂— 2-OMe-phenyl OMe Me CH N N O I-262 COOH phenyl—CH₂—CH₂— 2-OMe-4-Br-phenyl Me Me CH N N O I-263 COOH phenyl —CH₂—CH₂—3-OMe-phenyl Me Me CH N N O I-264 COOH phenyl —CH₂—CH₂— 3-OMe-phenyl MeMe N N N O I-265 COOH phenyl —CH₂—CH₂— 2-OMe-phenyl Me Me N N CH O I-266COOH phenyl —CH₂—CH₂—CH₂— 4-Et-phenyl OMe O—CH₂—CH₂—C N N O I-267 COOHphenyl —CH₂—CH₂—CH₂— 4-Cl-phenyl CF₃ Me CH N N O I-268 COOH phenyl—CH₂—CH₂— 2-OMe-phenyl ethyl Me CH N N S I-269 COOH phenyl —CH₂—CH₂—3,4,5-tri-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-270 COOH phenyl —CH₂—CH₂—4-SMe-phenyl CF₃ Me CH N N O I-271 COOH phenyl —CH═CH—CH₂— 4-OMe-phenylMe Me N N N O I-272 COOH phenyl —CH═CH—CH₂— 4-OMe-phenyl ethyl Me CH N NO I-273 COOH 4-Br-phenyl —CH₂—CH₂— 2-OMe-phenyl OMe CH₂—CH₂—CH₂—C N N OI-274 COOH phenyl —CH(OH)—CH₂— 2-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-275COOH 4-Et-phenyl —CH₂—CH₂— 4-Me-phenyl OMe O—CH₂—CH₂—C N N O I-276 COOH4-CF₃-phenyl —CH₂—CH₂— 4-OMe-phenyl OMe Me CH N N O I-277 COOH4-Cl-phenyl —CH(4-OMe-phenyl)—CH₂— 4-OMe-phenyl OMe Me CH N N O I-278COOH 4-Cl-phenyl —CH₂—CH₂— 3-Me-4-OMe-phenyl Me Me CH N N O I-279 COOH4-Cl-phenyl —CH₂—CH₂— 3,4-methylenedioxyphenyl Me Me CH N N O I-280 COOH4-Cl-phenyl —CH₂—CH₂— 3,4-methylenedioxyphenyl Me Me N N N O I-281 COOH4-Cl-phenyl —CH₂—CH₂— 4-OMe-phenyl ethyl Me N N N O I-282 COOH phenyl—CH₂—CH₂—CH₂— 4-Et-phenyl ethyl Me CH N N O I-283 COOH phenyl—CH₂—CH₂—CH₂— 4-Et-phenyl OMe CH₂—CH₂—CH₂—C N N O I-284 COOH phenyl—CH₂—CH₂— 4-Et-phenyl OMe CH₂—CH₂—CH₂—C N N O I-285 COOH phenyl—CH₂—CH₂— 4-Et-phenyl OMe O—CH₂—CH₂—C N N O I-286 COOH 4-Cl-phenyl—CH₂—CH₂— 4-OMe-phenyl ethyl Me CH N N S I-287 COOH phenyl —CH═CH—CH₂—4-OMe-phenyl OMe Me CH N N O I-288 COOH phenyl —CH═CH—CH₂— 4-OMe-phenylMe Me CH N N O I-289 COOH 3,4-di-Cl-phenyl —CH₂—CH₂— 4-OMe-phenyl OMeO—CH₂—CH₂—C N N O I-290 COOEt 4-Cl-phenyl —CH(OH)—CH₂— 3,4-di-OMe-phenylOMe Me CH N N O I-291 COOH 4-Et-phenyl —CH₂—CH₂— 4-Me-phenyl Me Me N N NO I-292 COOH 4-Et-phenyl —CH₂—CH₂— 4-Me-phenyl ethyl Me CH N N O I-293COOH phenyl —CH₂—CH₂— 3-OMe-phenyl CF₃ Me CH N N O I-294 COOH phenyl—CH₂—CH₂— 3-OMe-phenyl OMe Me CH N N O I-295 COOH 4-Cl-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl Me Me CH N CH O I-296 COOH 4-Cl-phenyl —C(CH₃)₂—CH₂—3,4-di-OMe-phenyl Me Me N N N O I-297 COOH phenyl —CH₂—CH₂—3,4,5-tri-OMe-phenyl ethyl Me CH N N O I-298 COOH phenyl —CH₂—CH₂—CH₂—4-Et-phenyl Me Me CH N N O I-299 COOH phenyl —CH₂—CH₂—CH₂— 4-Et-phenylMe Me N N N O I-300 COOH phenyl —CH₂—CH₂— 3,4,5-tri-OMe-phenyl OMeCH₂—CH₂—CH₂—C N N O I-301 COOH 4-Cl-phenyl —CH₂—CH₂— 3,4-di-OMe-phenylethyl Me N N N O I-302 COOH 3,4-di-Cl-phenyl —CH₂—CH₂— 3,4-di-OMe-phenylOMe O—CH₂—CH₂—C N N O I-303 COOH phenyl —CH₂—CH₂—CH₂—3,4,5-tri-OMe-phenyl OMe CH₂—CH₂—CH₂—C N N O I-304 COOH phenyl—CH═CH—CH₂— 4-OMe-phenyl CF₃ Me CH N N O I-305 COOH 4-Cl-phenyl—CH₂—CH₂— 3-Me-4-Et-phenyl OMe Me CH N N O I-306 COOH 4-Cl-phenyl—CH₂—CH₂— 3-Me-4-Et-phenyl SMe Me CH N N O I-307 COOH 4-Et-phenyl—CH₂—CH₂— 4-Me-phenyl OMe Me CH N N O I-308 COOH 4-Et-phenyl —CH₂—CH₂—4-Me-phenyl Me Me CH N N O I-309 COOH 4-Cl-phenyl —CH₂—CH₂— 4-iPr-phenylOMe O—CH₂—CH₂—C N N O I-310 COOH 4-Cl-phenyl —CH₂—CH₂—3,4-methylenedioxyphenyl OMe Me CH N N O I-311 COOH 4-Cl-phenyl—CH₂—CH₂— 4-Br-phenyl Me Me N N N O I-312 COOH phenyl —CH₂—CH₂—4-Et-phenyl Me Me N N N O I-313 COOH phenyl —CH₂—CH₂— 4-Et-phenyl ethylMe CH N N O I-314 COOH phenyl —CH₂—CH₂—CH₂— 4-Et-phenyl CF₃ Me CH N N OI-315 COOH phenyl —CH₂—CH₂—CH₂— 4-Et-phenyl OMe Me CH N N O I-316 COOH4-Cl-phenyl —CH₂—CH₂— 4-Br-phenyl ethyl Me N N N O I-317 COOH4-Cl-phenyl —CH(4-Br-phenyl)—CH₂— 4-Br-phenyl OMe O—CH₂—CH₂—C N N OI-318 COOH 4-Cl-phenyl —CH(OH)—CH₂— 4-SMe-phenyl OMe Me CH N N O I-319COOH phenyl —CH₂—CH₂—CH₂— 3,4,5-tri-OMe-phenyl Me Me N N N O I-320 COOHphenyl —CH₂—CH₂—CH₂— 3,4,5-tri-OMe-phenyl ethyl Me CH N N O I-321 COOHphenyl —CH₂—CH₂— 3,5-di-OMe-phenyl OMe CH₂—CH₂—CH₂—C N N O I-322 COOHphenyl —CH₂—CH₂— 3,5-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-323 COOH4-Et-phenyl —CH₂—CH₂— 4-SMe-phenyl ethyl Me CH N N O I-324 COOH4-Et-phenyl —CH₂—CH₂— 4-SMe-phenyl OMe O—CH₂—CH₂—C N N O I-325 COOH4-Cl-phenyl —C(CH₃)₂—CH₂— 4-SMe-phenyl Me Me CH N CH O I-326 COOH4-Cl-phenyl —CH₂—CH₂— 4-SMe-phenyl Me Me N N N S I-327 COOH phenyl—CH₂—CH₂— 3,4,5-tri-OMe-phenyl Me Me CH N N O I-328 COOH phenyl—CH₂—CH₂— 3,4,5-tri-OMe-phenyl Me Me N N N O I-329 COOH 4-Cl-phenyl—O—CH₂—CH₂— 4-SMe-phenyl ethyl Me CH N N O I-330 COOH phenyl—CH₂—CH₂—CH₂— 4-Me-phenyl ethyl Me CH N N O I-331 COOH phenyl—CH₂—CH₂—CH₂— 4-Me-phenyl OMe O—CH₂—CH₂—C N N O I-332 COOH 4-Cl-phenyl—CH₂—CH₂— 4-SMe-phenyl OMe O—CH═CH—C N N O I-333 COOH 4-Cl-phenyl—CH(OH)—CH₂— 4-OEt-3-OMe-phenyl OMe Me CH N N O I-334 COOH 4-Cl-phenyl—CH(4-SMe-phenyl)—CH₂— 4-SMe-phenyl Me Me CH N N O I-335 COOH phenyl—CH₂—CH₂—CH₂— 3,4,5-tri-OMe-phenyl OMe Me CH N N O I-336 COOH phenyl—CH₂—CH₂—CH₂— 3,4,5-tri-OMe-phenyl Me Me CH N N O I-337 COOH 4-Cl-phenyl—CH₂—CH₂— 4-iPr-phenyl Me Me N N N O I-338 COOH 4-Cl-phenyl —CH₂—CH₂—4-iPr-phenyl ethyl Me CH N N O I-339 COOH 4-Me-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl Me Me CH N N O I-340 COOH 4-Me-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl Me Me N N N O I-341 COOH 3,4-di-Cl-phenyl —CH₂—CH₂—4-OEt-3-OMe-phenyl Me Me N N N O I-342 COOH phenyl —CH₂—CH₂— 4-Et-phenylOMe Me CH N N O I-343 COOH phenyl —CH₂—CH₂— 4-Et-phenyl Me Me CH N N OI-344 COOH 4-Cl-phenyl —CH₂—CH₂— 4-OEt-3-OMe-phenyl ethyl Me CH N N SI-345 COOH 4-Cl-phenyl —CH(4-Me-phenyl)—CH₂— 4-Me-phenyl OMe Me CH N N OI-346 COOH phenyl —CH₂—CH₂—CH₂— 4-Me-phenyl Me Me CH N N O I-347 COOHphenyl —CH₂—CH₂—CH₂— 4-Me-phenyl Me Me N N N O I-348 COOMe 4-Cl-phenyl—CH₂—CH₂— 4-Me-phenyl Me Me CH N CH O I-349 COOH phenyl —CH₂—CH₂—3,5-di-OMe-phenyl Me Me N N N O I-350 COOH phenyl —CH₂—CH₂—3,5-di-OMe-phenyl ethyl Me CH N N O I-351 COOH phenyl —CH₂—CH₂—CH₂—2-Cl-phenyl OMe CH₂—CH₂—CH₂—C N N O I-352 COOH phenyl —CH₂—CH₂—CH₂—3,4,5-tri-OMe-phenyl CF₃ Me CH N N O I-353 COOH 4-Cl-phenyl —CH(OH)—CH₂—4-Me-phenyl Me Me N N N O I-354 COOH 4-Cl-phenyl —CH₂—CH₂—3,4-di-Me-phenyl ethyl Me CH N N O I-355 COOH 4-Me-phenyl —CH₂—CH₂—4-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-356 COOH 4-Me-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl OMe Me CH N N O I-357 COOH phenyl —CH₂—CH₂—3,4,5-tri-OMe-phenyl OMe OMe CH N N O I-358 COOH phenyl —CH₂—CH₂—3,4,5-tri-OMe-phenyl OMe Me CH N N O I-359 COOH 4-Cl-phenyl —CH₂—CH₂—4-Me-phenyl OMe O—CH₂—CH₂—C N N S I-360 COOH 4-Cl-phenyl —CH₂—CH₂—4-Et-phenyl OMe Me CH N N S I-361 COOH 4-Cl-phenyl —CH₂—CH₂— 4-Et-phenylMe Me CH N CH O I-362 COOH phenyl —CH₂—CH₂—CH₂— 4-Me-phenyl CF₃ Me CH NN O I-363 COOH phenyl —CH₂—CH₂—CH₂— 4-Me-phenyl OMe Me CH N N O I-364COOH 4-Cl-phenyl —CH₂—CH₂— 4-Et-phenyl ethyl Me N N N O I-365 COOH4-Cl-phenyl —CH₂—CH₂— 4-iPr-phenyl OMe Me CH N N O I-366 COOH4-Cl-phenyl —CH₂—CH₂— 4-iPr-phenyl Me Me CH N N O I-367 COOH phenyl—CH₂—CH₂—CH₂— 2-Cl-phenyl Me Me N N N O I-368 COOH phenyl —CH₂—CH₂—CH₂—2-Cl-phenyl ethyl Me CH N N O I-369 COOH 4-Cl-phenyl —CH₂—CH₂—4-Et-phenyl SMe Me CH N N O I-370 COOH phenyl —CH₂—CH₂— 4-Me-phenyl OMeO—CH₂—CH₂—C N N O I-371 COOH 4-Me-phenyl —CH₂—CH₂— 4-OMe-phenyl Me Me NN N O I-372 COOH 4-Me-phenyl —CH₂—CH₂— 4-OMe-phenyl ethyl Me CH N N OI-373 COOH phenyl —CH₂—CH₂— 4-Et-phenyl CF₃ Me CH N N O I-374 COOH4-Cl-phenyl —C(CH₃)₂—CH₂— 4-Et-phenyl OMe O—CH₂—CH₂—C N N O I-375 COOH4-Cl-phenyl —CH₂—CH₂— 4-Cl-phenyl OMe Me CH N N S I-376 COOH 4-Cl-phenyl—CH₂—CH₂— 1-Me-naphth-2-yl OMe Me CH N N O I-377 COOH phenyl —CH₂—CH₂—3,5-di-OMe-phenyl OMe Me CH N N O I-378 COOH phenyl —CH₂—CH₂—CH₂—3,4-methylenedioxyphenyl ethyl Me CH N N O I-379 COOH phenyl—CH₂—CH₂—CH₂— 3,4-methylenedioxyphenyl OMe O—CH₂—CH₂—C N N O I-380 COOHphenyl —CH₂—CH₂— 3,5-di-OMe-phenyl Me Me CH N N O I-381 COOH 4-Cl-phenyl—CH(4-OEt-phenyl)—CH₂— 4-OEt-phenyl OMe Me CH N N O I-382 COOH4-Cl-phenyl —CH(OH)—CH₂— 4-OEt-phenyl Me Me CH N N O I-383 COOH phenyl—CH₂—CH₂—CH₂— 2-Cl-phenyl OMe Me CH N N O I-384 COOH phenyl—CH₂—CH₂—CH₂— 2-Cl-phenyl Me Me CH N N O I-385 COOH phenyl —CH₂—CH₂—3,4-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-386 COOH phenyl —CH₂—CH₂—3,4,5-tri-OMe-phenyl CF₃ Me CH N N O I-387 COOH 4-Me-phenyl —CH₂—CH₂—4-OMe-phenyl OMe Me CH N N O I-388 COOH 4-Me-phenyl —CH₂—CH₂—4-OMe-phenyl Me Me CH N N O I-389 COOH 4-Cl-phenyl —CH₂—CH₂—4-OEt-phenyl ethyl Me N N CH O I-390 COOH 3,4-di-Cl-phenyl —CH₂—CH₂—3,5-di-OMe-phenyl OMe Me CH N N O I-391 COOH 4-Cl-phenyl —CH₂—CH₂—3,5-di-OMe-4-Cl-phenyl Me Me CH N N O I-392 COOH 4-Cl-phenyl —CH₂—CH₂—3,5-di-OMe-phenyl Me Me N N CH O I-393 COOH 4-Cl-phenyl —CH₂—CH₂—4-OEt-3-OMe-phenyl ethyl Me CH N N O I-394 COOH phenyl —CH₂—CH₂—CH₂—3,4-methylenedioxyphenyl Me Me CH N N O I-395 COOH phenyl —CH₂—CH₂—CH₂—3,4-methylenedioxyphenyl Me Me N N N O I-396 COOH 4-Cl-phenyl —CH₂—CH₂—4-OEt-3-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-397 COOH 4-Cl-phenyl—C(CH₃)₂—CH₂— 3-OMe-phenyl CF₃ Me CH N N O I-398 COOH phenyl —CH₂—CH₂—4-Me-phenyl ethyl Me CH N N O I-399 COOH 4-Me-phenyl —CH₂—CH₂—CH₂—4-Me-phenyl ethyl Me CH N N O I-400 COOH phenyl —CH₂—CH₂—CH₂—2-Cl-phenyl CF₃ Me CH N N O I-401 COOH phenyl —CH₂—CH₂— 4-Me-phenyl OMeCH₂—CH₂—CH₂—C N N O I-402 COOH 4-Cl-phenyl —C(CH₃)₂—CH₂— 3-OMe-phenyl MeMe CH N N O I-403 COOH 4-CF₃-phenyl —CH₂—CH₂— 4-Me-phenyl ethyl Me CH NN O I-404 COOH 4-CF₃-phenyl —CH₂—CH₂— 4-Me-phenyl OMe O—CH₂—CH₂—C N N OI-405 COOH 4-Et-phenyl —CH₂—CH₂— 4-OMe-phenyl OMe Me CH N N S I-406 COOH4-Et-phenyl —CH₂—CH₂— 3-Me-4-OMe-phenyl Me Me CH N N O I-407 COOH phenyl—CH₂—CH₂— 4-OEt-phenyl OMe O—CH₂—CH₂—C N N O I-408 COOH phenyl —CH₂—CH₂—3,5-di-OMe-phenyl CF₃ Me CH N N O I-409 COOH 4-Et-phenyl —CH₂—CH₂—3-Me-4-OMe-phenyl Me Me N N CH O I-410 COOH phenyl —CH₂—CH₂—CH₂—3,4-methylenedioxyphenyl CF₃ Me CH N N O I-411 COOH phenyl —CH₂—CH₂—CH₂—3,4-methylenedioxyphenyl OMe Me CH N N O I-412 COOH 4-Et-phenyl—CH₂—CH₂— 4-OMe-phenyl ethyl Me CH CH N O I-413 COOH phenyl —CH₂—CH₂—3,4-di-OMe-phenyl ethyl Me CH N N O I-414 COOH phenyl —CH₂—CH₂—3,4-di-OMe-phenyl OMe CH₂—CH₂—CH₂—C N N O I-415 COOH 4-Me-phenyl—CH₂—CH₂—CH₂— 4-Me-phenyl Me Me CH N N O I-416 COOH 4-Me-phenyl—CH₂—CH₂—CH₂— 4-Me-phenyl Me Me N N N O I-417 COOH 4-Et-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl SMe Me CH N N O I-418 COOMe 4-Et-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl Me Me CH N N O I-419 COOH 4-CF₃-phenyl —CH₂—CH₂—4-Me-phenyl Me Me CH N N O I-420 COOH 4-CF₃-phenyl —CH₂—CH₂— 4-Me-phenylMe Me N N N O I-421 COOH 4-Et-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl Me Me NN N S I-422 COOH 4-Et-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl ethyl Me CH CHN O I-423 COOH 4-Cl-phenyl —CH₂—CH₂— 4-OEt-3-OMe-phenyl Me Me CH N N OI-424 COOH 4-Cl-phenyl —CH₂—CH₂— 4-OEt-3-OMe-phenyl Me Me N N N O I-425COOH 4-Et-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl OMe O—CH═CH—C N N O I-426COOH phenyl —CH₂—CH₂—CH₂— 4-SMe-phenyl ethyl Me CH N N O I-427 COOHphenyl —CH₂—CH₂—CH₂— 4-SMe-phenyl OMe O—CH₂—CH₂—C N N O I-428 COOHphenyl —CH₂—CH₂— 4-Me-phenyl Me Me CH N N O I-429 COOH phenyl —CH₂—CH₂—4-Me-phenyl Me Me N N N O I-430 COOH 4-Et-phenyl —CH₂—CH₂— 3-OMe-phenylOMe CF₃ CH N N O I-431 COOH 4-Me-phenyl —CH₂—CH₂—CH₂— 4-SMe-phenyl OMeMe CH N N O I-432 COOH 4-Me-phenyl —CH₂—CH₂—CH₂— 4-SMe-phenyl OMeO—CH₂—CH₂—C N N O I-433 COOH 4-Et-phenyl —CH(3-OMe-phenyl)—CH₂—3-OMe-phenyl Me Me CH N N O I-434 COOH 4-Cl-phenyl —CH₂—CH₂— naphth-2-ylMe Me CH N N O I-435 COOH 4-CF₃-phenyl —CH₂—CH₂— 4-SMe-phenyl OMeO—CH₂—CH₂—C N N O I-436 COOH 4-CF₃-phenyl —CH₂—CH₂— 4-Me-phenyl OMe MeCH N N O I-437 COOH 4-Cl-phenyl —CH₂—CH₂— naphth-2-yl Me Me N N N OI-438 COOH 4-Et-phenyl —CH(OH)—CH₂— 3-OMe-phenyl Me Me N N N O I-439COOH phenyl —CH₂—CH₂— 4-OEt-phenyl ethyl Me CH N N O I-440 COOH phenyl—CH₂—CH₂— 4-OEt-phenyl OMe CH₂—CH₂—CH₂—C N N O I-441 COOH 4-Et-phenyl—CH₂—CH₂— 3-OMe-phenyl Me Me CH N CH O I-442 COOH phenyl —CH₂—CH₂—CH₂—4-SMe-phenyl Me Me CH N N O I-443 COOH phenyl —CH₂—CH₂—CH₂— 4-SMe-phenylMe Me N N N O I-444 COOH 4-Et-phenyl —C(CH₃)₂—CH₂— 3-OMe-phenyl OMeO—CH₂—CH₂—C N N O I-445 COOH phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl Me Me CHN N O I-446 COOH phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl Me Me N N N O I-447COOH 4-Me-phenyl —CH₂—CH₂—CH₂—- 3,4-di-OMe-phenyl ethyl Me CH N N OI-448 COOH 4-Me-phenyl —CH₂—CH₂—CH₂— 3-OMe-phenyl OMe O—CH₂—CH₂—C N N OI-449 COOH 4-Et-phenyl —CH₂—CH₂— 4-SMe-phenyl OMe Me CH N N S I-450 COOH4-Cl-phenyl —CH₂—CH₂— 2-OMe-phenyl Me Me CH N N O I-451 COOH4-CF₃-phenyl —CH₂—CH₂— 4-SMe-phenyl Me Me N N N O I-452 COOH4-CF₃-phenyl —CH₂—CH₂— 4-SMe-phenyl ethyl Me CH N N O I-453 COOH4-Cl-phenyl —CH₂—CH₂— 2-OMe-phenyl Me Me N N N O I-454 COOBzl4-Et-phenyl —CH₂—CH₂— 4-SMe-phenyl Me Me CH N N O I-455 COOH 4-Et-phenyl—CH₂—CH₂— 4-SMe-phenyl ethyl Me CH CH N O I-456 COOH 4-Et-phenyl—CH₂—CH₂— 4-Me-phenyl OMe Me N N N O I-457 COOH 4-Cl-phenyl —CH₂—CH₂—4-SMe-phenyl OMe O—CH₂—CH₂—C N N O I-458 COOH phenyl —CH₂—CH₂—CH₂—4-SMe-phenyl CF₃ Me CH N N O I-459 COOH phenyl —CH₂—CH₂—CH₂—4-SMe-phenyl OMe Me CH N N O I-460 COOH 4-Cl-phenyl —CH₂—CH₂—4-OEt-3-OMe-phenyl OMe Me CH N N O I-461 COOH 4-CF₃-phenyl —CH₂—CH₂—4-OMe-phenyl Me Me N CH N O I-462 COOH phenyl —CH₂—CH₂— 4-Me-phenyl CF₃Me CH N N O I-463 COOH 4-Me-phenyl —CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl OMeMe CH N N O I-464 COOH 4-Me-phenyl —CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl Me MeCH N N O I-465 COOH phenyl —CH₂—CH₂— 4-Me-phenyl OMe Me CH N N O I-466COOH 4-CF₃-phenyl —C(CH₃)₂—CH₂— 4-OMe-phenyl ethyl Me CH N N O I-467COOH 4-CF₃-phenyl —CH₂—CH₂— 4-SMe-phenyl OMe Me CH N N O I-468 COOH4-CF₃-phenyl —CH₂—CH₂— 4-SMe-phenyl Me Me CH N N O I-469 COOH4-CF₃-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl ethyl Me CH CH N O I-470 COOH4-Cl-phenyl —CH₂—CH₂— 4-Cl-phenyl OMe O—CH₂—CH₂—C N N O I-471 COOH4-Cl-phenyl —CH₂—CH₂— naphth-2-yl OMe Me CH N N O I-472 COOH4-CF₃-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl OMe O—CH₂—CH₂—C N N S I-473COOH phenyl —CH₂—CH₂— 4-OEt-phenyl Me Me CH N N O I-474 COOH phenyl—CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl ethyl Me CH N N O I-475 COOH phenyl—CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-476 COOH phenyl—CH₂—CH₂— 4-OEt-phenyl Me Me N N N O I-477 COOH 4-CF₃-phenyl —CH₂—CH₂—3-OMe-phenyl ethyl Me N N N O I-478 COOH 4-CF₃-phenyl —CH₂—CH₂—2-Me-3-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-479 COOH 4-Me-phenyl—CH₂—CH₂—CH₂— 4-OMe-phenyl ethyl Me CH N N O I-480 COOH 4-Me-phenyl—CH₂—CH₂—CH₂— 4-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-481 COOH phenyl—CH₂—CH₂— 3,4-di-OMe-phenyl OMe OMe CH N N O I-482 COOH phenyl —CH₂—CH₂—3,4-di-OMe-phenyl OMe Me CH N N O I-483 COOH 4-CF₃-phenyl —CH₂—CH₂—3-OMe-phenyl ethyl Me CH N N O I-484 COOH 4-CF₃-phenyl —CH₂—CH₂—3-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-485 COOH 4-CF₃-phenyl —CH₂—CH₂—3-Me-4-SMe-phenyl OMe Me CH N N O I-486 COOH 4-Cl-phenyl —CH₂—CH₂—3-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-487 COOH 4-Cl-phenyl —CH₂—CH₂—2-OMe-phenyl OMe Me CH N N O I-488 COOH 4-CF₃-phenyl —CH₂—CH₂—cyclohexyl OMe Me CH N N O I-489 COOH 4-CF₃-phenyl —CH₂—CH₂— 4-Me-phenylMe Me CH N N S I-490 COOH phenyl —CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl Me MeCH N N O I-491 COOH phenyl —CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl Me Me N N N OI-492 COOH 4-Me-phenyl —CH₂—CH₂— cyclohexyl OMe Me CH N N O I-493 COOH4-Cl-phenyl —CH₂—CH₂— 4-SMe-phenyl Me Me N N N O I-494 COOH 4-Cl-phenyl—CH₂—CH₂— 4-SMe-phenyl ethyl Me CH N N O I-495 COOH 4-CF₃-phenyl—CH₂—CH₂—CH₂— 4-Me-phenyl OMe O—CH₂—CH₂—C N N O I-496 COOH 4-Me-phenyl—CH₂—CH₂—CH₂— 4-OMe-phenyl OMe Me CH N N O I-497 COOH 4-Me-phenyl—CH₂—CH₂— 4-OMe-phenyl Me Me CH N N S I-498 COOH phenyl —CH₂—CH₂—3,4-methylenedioxyphenyl OMe CH₂—CH₂—CH₂—C N N O I-499 COOH phenyl—CH₂—CH₂—CH₂— phenyl OMe Me CH N N O I-500 COOH phenyl —CH₂—CH₂—CH₂—phenyl Me Me CH N N O I-501 COOH phenyl —CH₂—CH₂—3,4-methylenedioxyphenyl OMe O—CH₂—CH₂—C N N O I-502 COOH 4-Me-phenyl—CH₂—CH₂— 3,4-di-OMe-phenyl Me Me N CH N O I-503 COOH 4-Me-phenyl—CH₂—CH₂— 3,4-di-OMe-phenyl ethyl Me CH N N S I-504 COOH 4-Cl-phenyl—CH₂—CH₂— 4-Cl-phenyl Me Me N N N O I-505 COOH 4-Cl-phenyl —CH₂—CH₂—4-Cl-phenyl ethyl Me CH N N O I-506 COOH phenyl —CH₂—CH₂—CH₂—3,4-di-OMe-phenyl CF₃ Me CH N N O I-507 COOH phenyl —CH₂—CH₂—CH₂—3,4-di-OMe-phenyl OMe Me CH N N O I-508 COOH 4-Me-phenyl —CH₂—CH₂—cyclopentyl OMe Me CH N N O I-509 COOH phenyl —CH₂—CH₂— 4-OEt-phenyl CF₃Me CH N N O I-510 COOH phenyl —CH₂—CH₂— 4-OEt-phenyl OMe Me CH N N OI-511 COOH 4-CF₃-phenyl —CH₂—CH₂—CH₂— 4-Me-phenyl Me Me N N N O I-512COOH 4-CF₃-phenyl —CH₂—CH₂—CH₂— 4-Me-phenyl ethyl Me CH N N O I-513 COOH4-Me-phenyl —CH₂—CH₂— 4-SMe-phenyl OMe Me CH N N S I-514 COOH4-Me-phenyl —CH₂—CH₂— 4-SMe-phenyl ethyl Me N N N O I-515 COOH4-Me-phenyl —CH₂—CH₂— 4-Me-phenyl OMe O—CH₂—CH₂—C N N O I-516 COOHphenyl —CH₂—CH₂—CH₂— phenyl CF₃ Me CH N N O I-517 COOH phenyl —CH₂—CH₂—4-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-518 COOH phenyl —CH₂—CH₂—3,4-di-OMe-phenyl CF₃ Me CH N N O I-519 COOH 4-Me-phenyl —CH₂—CH₂—4-SMe-phenyl ethyl Me CH CH N O I-520 COOH 4-Cl-phenyl —CH₂—CH₂—3-OMe-phenyl Me Me N N N O I-521 COOH 4-Cl-phenyl —CH₂—CH₂— 3-OMe-phenylethyl Me CH N N O I-522 COOH phenyl —CH₂—CH₂—CH₂— 4-OMe-phenyl OMeCH₂—CH₂—CH₂—C N N O I-523 COOH phenyl —CH₂—CH₂—CH₂— 4-OMe-phenyl OMeO—CH₂—CH₂—C N N O I-524 COOMe 4-Me-phenyl —CH₂—CH₂— 4-Me-phenyl OMeO—CH₂—CH₂—C N N O I-525 COOMe phenyl —CH₂—CH₂—CH₂— phenyl CF₃ Me CH N NO I-526 COOH phenyl —CH₂—CH₂—CH₂— phenyl OMe Me CH N N S I-527 COOH4-CF₃-phenyl —CH₂—CH₂—CH₂— 4-SMe-phenyl ethyl Me CH N N O I-528 COOH4-CF₃-phenyl —CH₂—CH₂—CH₂— 4-SMe-phenyl OMe O—CH₂—CH₂—C N N O I-529 COOH4-Cl-phenyl —CH₂—CH₂— 4-SMe-phenyl OMe Me CH N N O I-530 COOH4-Cl-phenyl —CH₂—CH₂— 4-SMe-phenyl Me Me CH N N O I-531 COOH 4-Me-phenyl—CH₂—CH₂— 4-Me-phenyl Me Me N N N O I-532 COOH 4-Me-phenyl —CH₂—CH₂—4-Me-phenyl ethyl Me CH N N O I-533 COOH phenyl —CH₂—CH₂—CH₂— 4-F-phenylMe Me CH N N O I-534 COOH phenyl —CH₂—CH₂— 3,4-methylenedioxyphenyl MeMe N N N O I-535 COOH phenyl —CH₂—CH₂— 3,4-methylenedioxyphenyl ethyl MeCH N N O I-536 COOH phenyl —CH₂—CH₂—CH₂— phenyl Me Me N N CH O I-537COOH 4-Br-phenyl —CH₂—CH₂—CH₂— phenyl ethyl Me CH N N O I-538 COOHphenyl —CH₂—CH₂—CH₂— 4-OMe-phenyl Me Me N N N O I-539 COOH phenyl—CH₂—CH₂—CH₂— 4-OMe-phenyl ethyl Me CH N N O I-540 COOH 4-Cl-phenyl—CH₂—CH₂— 4-Cl-phenyl OMe Me CH N N O I-541 COOH 4-Cl-phenyl —CH₂—CH₂—4-Cl-phenyl Me Me CH N N O I-542 COOH 4-F-phenyl —CH₂—CH₂—CH₂— phenylOMe O—CH₂—CH₂—C N N O I-543 COOH 4-CF₃-phenyl —CH₂—CH₂—CH₂— 3-OMe-phenylOMe O—CH₂—CH₂—C N N O I-544 COOH 4-CF₃-phenyl —CH₂—CH₂—CH₂— 4-SMe-phenylOMe Me CH N N O I-545 COOH phenyl —CH₂—CH₂— naphth-2-yl OMeCH₂—CH₂—CH₂—C N N O I-546 COOH phenyl —CH₂—CH₂— naphth-2-yl OMeO—CH₂—CH₂—C N N O I-547 COOH 4-Me-phenyl —CH₂—CH₂— 4-Me-phenyl OMe Me CHN N O I-548 COOH 4-Me-phenyl —CH₂—CH₂— 4-Me-phenyl Me Me CH N N O I-549COOMe phenyl —CH(phenyl)—CH₂—CH₂— phenyl CF₃ Me CH N N O I-550 COOH4-F-phenyl —CH(phenyl)—CH₂—CH₂— phenyl OMe Me CH N N O I-551 COOH phenyl—CH₂—CH₂— 4-OMe-phenyl ethyl Me CH N N O I-552 COOH phenyl —CH₂—CH₂—4-OMe-phenyl OMe CH₂—CH₂—CH₂—C N N O I-553 COOH phenyl—CH(phenyl)—CH₂—CH₂— phenyl Me Me CH CH N O I-554 COOH phenyl—CH₂—CH₂—CH₂— 4-OMe-phenyl OMe Me CH N N O I-555 COOH phenyl—CH₂—CH₂—CH₂— 4-OMe-phenyl Me Me CH N N O I-556 COOH 4-Cl-phenyl—CH₂—CH₂— 3-OMe-phenyl OMe Me CH N N O I-557 COOH 4-Cl-phenyl —CH₂—CH₂—3-OMe-phenyl Me Me CH N N O I-558 COOH phenyl —CH(phenyl)—CH₂—CH₂—phenyl OMe Me N N N O I-559 COOH 4-CF₃-phenyl —CH₂—CH₂—CH₂—3,4-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-560 COOH 4-CF₃-phenyl—CH₂—CH₂—CH₂— 3-OMe-phenyl ethyl Me CH N N O I-561 COOH phenyl—CH(phenyl)—CH₂—CH₂— phenyl ethyl Me N N N O I-562 COOMe phenyl—CH₂—CH₂—CH₂— 4-OMe-phenyl CF₃ Me CH N N O I-563 COOH 4-Me-phenyl—CH₂—CH₂— 4-SMe-phenyl ethyl Me CH N N O I-564 COOH 4-Me-phenyl—CH₂—CH₂— 4-SMe-phenyl OMe O—CH₂—CH₂—C N N O I-565 COOH 4-Cl-phenyl—CH₂—CH₂— 3,4,5-tri-OMe-phenyl ethyl Me CH N N O I-566 COOH 4-Cl-phenyl—CH₂—CH₂— 3,4,5-tri-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-567 COOH phenyl—CH₂—CH₂—CH₂— 4-OMe-phenyl OMe Me CH N N S I-568 COOH phenyl —CH₂—CH₂—3,4-methylenedioxyphenyl OMe Me CH N N O I-569 COOH phenyl —CH₂—CH₂—3,4-methylenedioxyphenyl Me Me CH N N O I-570 COOH phenyl—CH(phenyl)—CH₂—CH₂— phenyl OMe O—CH₂—CH₂—C N N O I-571 COOH phenyl—CH₂—CH₂—CH₂— 4-OMe-phenyl CF₃ Me CH N N O I-572 COOH phenyl—CH₂—CH₂—CH₂— 4-OMe-phenyl Me Me CH N CH O I-573 COOH phenyl—CH₂—CH₂—CH₂— 4-OMe-phenyl ethyl Me N N N O I-574 COOH 4-Cl-phenyl—CH₂—CH₂— 4-Et-phenyl ethyl Me CH N N O I-575 COOH 4-CF₃-phenyl—CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl OMe Me CH N N O I-576 COOH 4-CF₃-phenyl—CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl ethyl Me CH N N O I-577 COOH 4-Cl-phenyl—CH₂—CH₂— 4-Et-phenyl OMe O—CH₂—CH₂—C N N O I-578 COOH phenyl—CH₂—CH₂—CH₂— 3-Cl-4-OMe-phenyl ethyl Me CH N N O I-579 COOH 4-Me-phenyl—CH₂—CH₂— 4-SMe-phenyl Me Me CH N N O I-580 COOH 4-Me-phenyl —CH₂—CH₂—4-SMe-phenyl Me Me N N N O I-581 COOH phenyl —CH₂—CH₂— naphth-2-yl Me MeN N N O I-582 COOH phenyl —CH₂—CH₂— naphth-2-yl ethyl Me CH N N O I-583COOH 4-F-phenyl —CH₂—CH₂—CH₂— 4-OMe-phenyl OMe CH₂—CH₂—CH₂—C N N O I-584COOH 4-F-phenyl —CH₂—CH₂—CH₂— 4-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-585COOH phenyl —CH₂—CH₂— 4-OMe-phenyl Me Me CH N N O I-586 COOH phenyl—CH(phenyl)—CH₂—CH₂— phenyl Me Me N N N O I-587 COOH phenyl—CH(phenyl)—CH₂—CH₂— phenyl ethyl Me CH N N O I-588 COOH phenyl—CH₂—CH₂— 4-OMe-phenyl Me Me N N N O I-589 COOH 4-F-phenyl —CH₂—CH₂—CH₂—3,4-di-OMe-phenyl CF₃ Me CH N N O I-590 COOH 4-Cl-phenyl —CH₂—CH₂—3,5-di-OMe-phenyl ethyl Me CH N N O I-591 COOH 4-Et-phenyl —CH₂—CH₂—CH₂—4-Me-phenyl OMe O—CH₂—CH₂—C N N O I-592 COOH 4- CF₃-phenyl —CH₂—CH₂—CH₂—4-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-593 COOH 4-Cl-phenyl —CH₂—CH₂—3,5-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-594 COOH phenyl—CH(OH)—CH(OH)—CH₂— 3,4-di-OMe-phenyl OMe Me CH N N O I-595 COOH4-Me-phenyl —CH₂—CH₂— 3-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-596 COOH4-Me-phenyl —CH₂—CH₂— 4-SMe-phenyl OMe Me CH N N O I-597 COOH phenyl—CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl Me Me CH N N S I-598 COOH phenyl—CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl Me Me N CH N O I-599 COOH 4-Cl-phenyl—CH₂—CH₂— 3,4,5-tri-OMe-phenyl Me Me CH N N O I-600 COOH 4-Cl-phenyl—CH₂—CH₂— 3,4,5-tri-OMe-phenyl Me Me N N N O I-601 COOEt phenyl—CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl ethyl Me CH N N O I-602 COOH phenyl—CH(phenyl)—CH₂—CH₂— phenyl OMe Me CH N N O I-603 COOH phenyl—CH(phenyl)—CH₂—CH₂— phenyl Me Me CH N N O I-604 COOH phenyl —CH₂—CH₂—4-iPr-phenyl OMe O—CH₂—CH₂—C N N O I-605 COOH phenyl —CH₂—CH₂—3,4-methylenedioxyphenyl CF₃ Me CH N N O I-606 COOH phenyl —CH₂—CH₂—CH₂—3,4-di-OMe-phenyl OMe O—CH₂—CH₂—C N N S I-607 COOH 4-Et-phenyl—CH₂—CH₂—CH₂— 4-SMe-phenyl OMe O—CH₂—CH₂—C N N O I-608 COOH 4-Et-phenyl—CH₂—CH₂—CH₂— 4-Me-phenyl OMe Me CH N N O I-609 COOH 4-Br-phenyl—CH₂—CH₂—CH₂— 4-SMe-phenyl OMe Me CH N N O I-610 COOH 4-Cl-phenyl—CH₂—CH₂— 4-Et-phenyl Me Me CH N N O I-611 COOH 4-Me-phenyl —CH₂—CH₂—3-OMe-phenyl Me Me N N N O I-612 COOH 4-Me-phenyl —CH₂—CH₂— 3-OMe-phenylethyl Me CH N N O I-613 COOH 4-Cl-phenyl —CH₂—CH₂— 4-Et-phenyl Me Me N NN O I-614 COOH phenyl —CH₂—CH₂—CH₂— 4-SMe-phenyl ethyl Me N CH N O I-615COOH phenyl —CH₂—CH₂— naphth-2-yl OMe Me CH N N O I-616 COOH phenyl—CH₂—CH₂— naphth-2-yl Me Me CH N N O I-617 COOH phenyl—CH(OH)—CH(OH)—CH₂— 4-SMe-phenyl OMe O—CH₂—CH₂—C N N O I-618 COOH phenyl—CH₂—CH₂—CH₂— phenyl OMe O—CH₂—CH₂—C N N O I-619 COOH phenyl—CH(phenyl)—CH₂—CH₂— phenyl CF₃ Me CH N N O I-620 COOH phenyl—CH₂—CH₂—CH₂— 4-Me-phenyl Me Me N N CH O I-621 COOH phenyl —CH₂—CH₂—4-OMe-phenyl OMe OMe CH N N O I-622 COOH phenyl —CH₂—CH₂— 4-OMe-phenylOMe Me CH N N O I-623 COOH 4-Et-phenyl —CH₂—CH₂—CH₂— 4-SMe-phenyl Me MeCH N N O I-624 COOH 4-Et-phenyl —CH₂—CH₂—CH₂— 4-SMe-phenyl ethyl Me CH NN O I-625 COOH phenyl —CH₂—CH₂—CH₂— 4-Me-phenyl CF₃ Me CH N N S I-626COOH 4-Cl-phenyl —CH₂—CH₂— 3,5-di-OMe-phenyl Me Me CH N N O I-627 COOH4-Me-phenyl —CH₂—CH₂— 3-OMe-phenyl OMe Me CH N N O I-628 COOH4-Me-phenyl —CH₂—CH₂— 3-OMe-phenyl Me Me CH N N O I-629 COOH 4-Cl-phenyl—CH₂—CH₂— 3,5-di-OMe-phenyl Me Me N N N O I-630 COOH phenyl—CH₂—CH₂—CH₂— 4-Me-phenyl OMe Me N N N O I-631 COOH phenyl—CH(OH)—CH(OH)—CH₂— 4-Me-phenyl Me Me CH N N O I-632 COOH 4-Cl-phenyl—CH₂—CH₂—CH₂— 4-Et-phenyl ethyl Me CH N N O I-633 COOH 4-Cl-phenyl—CH₂—CH₂—CH₂— 4-Et-phenyl OMe O—CH₂—CH₂—C N N O I-634 COOH 4-F-phenyl—CH₂—CH₂—CH₂— 4-Me-phenyl Me Me N N N O I-635 COOH 4-Cl-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-636 COOH phenyl —CH₂—CH₂—CH₂—phenyl Me Me N N N O I-637 COOH phenyl —CH₂—CH₂—CH₂— phenyl ethyl Me CHN N O I-638 COOH 4-Cl-phenyl —CH₂—CH₂— 3,4,5-tri-OMe-phenyl OMe Me CH NN O I-639 COOH 4-F-phenyl —CH₂—CH₂—CH₂— 4-Me-phenyl ethyl Me CH N N OI-640 COOH phenyl —CH₂—CH₂— 4-iPr-phenyl ethyl Me CH N N O I-641 COOH4-Et-phenyl —CH₂—CH₂—CH₂— 3-OMe-phenyl ethyl Me CH N N O I-642 COOH4-Et-phenyl —CH₂—CH₂—CH₂— 3-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-643 COOHphenyl —CH₂—CH₂— 4-iPr-phenyl OMe CH₂—CH₂—CH₂—C N N O I-644 COOH4-F-phenyl —CH₂—CH₂—CH₂— 4-Me-phenyl OMe O—CH₂—CH₂—C N N O I-645 COOH4-Me-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl ethyl Me CH N N O I-646 COOH4-Me-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-647 COOH4-F-phenyl —CH₂—CH₂—CH₂— 4-Et-phenyl CF₃ Me CH N N O I-648 COOH4-Cl-phenyl —CH₂—CH₂— 4-Me-phenyl OMe O—CH₂—CH₂—C N N O I-649 COOH4-Cl-phenyl —CH₂—CH₂— 4-Et-phenyl OMe Me CH N N O I-650 COOMe phenyl—CH₂—CH₂—CH₂— 4-Et-phenyl OMe Me CH N N O I-651 COOH phenyl —CH₂—CH₂—4-Cl-phenyl OMe O—CH₂—CH₂—C N N O I-652 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂—4-Me-phenyl ethyl Me CH N N O I-653 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂—4-Et-phenyl OMe Me CH N N O I-654 COOH phenyl —CH₂—CH₂— naphth-2-yl CF₃Me CH N N O I-655 COOH phenyl —CH₂—CH₂—CH₂— 3,4-di-Cl-phenyl Me Me N N NO I-656 COOH 4-F-phenyl —CH₂—CH₂—CH₂— 4-Cl-phenyl ethyl Me CH N N OI-657 COOH phenyl —CH₂—CH₂— phenyl OMe O—CH₂—CH₂—C N N O I-658 COOHphenyl —CH₂—CH₂— 4-OMe-phenyl CF₃ Me CH N N O I-659 COOH 4-Et-phenyl—CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-660 COOH4-Et-phenyl —CH₂—CH₂—CH₂— 3-OMe-phenyl OMe Me CH N N O I-661 COOH phenyl—CH₂—CH₂—CH₂— 4-Cl-phenyl OMe CH₂—CH₂—CH₂—C N N S I-662 COOH 4-Cl-phenyl—CH₂—CH₂— 4-OEt-phenyl OMe O—CH₂—CH₂—C N N O I-663 COOH 4-Cl-phenyl—CH₂—CH₂— 3,5-di-OMe-phenyl OMe Me CH N N O I-664 COOH phenyl—CH₂—CH₂—CH₂— 3-OMe-phenyl ethyl Me N CH N O I-665 COOH phenyl—CH₂—CH₂—CH₂— 3-OMe-phenyl OMe Me N N N O I-666 COOH 4-Cl-phenyl—CH₂—CH₂—CH₂— 4-Me-phenyl OMe Me CH N N O I-667 COOH 4-Cl-phenyl—CH₂—CH₂—CH₂— 4-Me-phenyl Me Me N N N O I-668 COOH phenyl —CH₂—CH₂—CH₂—2,3-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-669 COOH 4-Cl-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl Me Me N N N O I-670 COOH 4-Cl-phenyl —CH₂—CH₂—3,4-di-OMe-phenyl ethyl Me CH N N O I-671 COOH 3,4-di-Cl-phenyl—CH₂—CH₂—CH₂— 4-OMe-phenyl OMe Me CH N N O I-672 COOH phenyl —CH₂—CH₂—4-iPr-phenyl Me Me CH N N O I-673 COOH 4-Et-phenyl —CH₂—CH₂—CH₂—3,4-di-OMe-phenyl Me Me CH N N O I-674 COOH 4-Et-phenyl —CH₂—CH₂—CH₂—3,4-di-OMe-phenyl ethyl Me CH N N O I-675 COOH phenyl —CH₂—CH₂—4-iPr-phenyl Me Me N N N O I-676 COOH 3,4-di-Cl-phenyl —CH₂—CH₂—CH₂—4-OMe-phenyl Me Me CH N N O I-677 COOH 3,4-di-Cl-phenyl —CH₂—CH₂—CH₂—4-OMe-phenyl ethyl Me CH N N O I-678 COOH 4-Cl-phenyl —CH₂—CH₂—4-Me-phenyl Me Me N N N O I-679 COOH 4-Cl-phenyl —CH₂—CH₂— 4-Me-phenylethyl Me CH N N O I-680 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂—3,4-methylenedioxyphenyl Me Me CH N N O I-681 COOH 4-Cl-phenyl—CH₂—CH₂—CH₂— 3,4-methylenedioxyphenyl OMe O—CH₂—CH₂—C N N O I-682 COOH3,4-di-Cl-phenyl —CH₂—CH₂—CH₂— 4-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-683COOH phenyl —CH₂—CH₂— 4-Cl-phenyl ethyl Me CH N N O I-684 COOH phenyl—CH₂—CH₂— 4-Cl-phenyl OMe CH₂—CH₂—CH₂—C N N O I-685 COOH phenyl—CH(OH)—CH(OH)—CH₂— 2-Cl-phenyl OMe Me CH N N O I-686 COOH phenyl—CH₂—CH₂—CH₂— 2-Cl-phenyl Me Me CH CH N O I-687 COOH 4-Et-phenyl—CH₂—CH₂—CH₂— 4-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-688 COOH 4-Et-phenyl—CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl OMe Me CH N N O I-689 COOH phenyl—CH₂—CH₂— phenyl Me Me N N N O I-690 COOH phenyl —CH₂—CH₂— phenyl ethylMe CH N N O I-691 COOH phenyl —CH₂—CH₂—CH₂— 2-Cl-phenyl Me Me N N N SI-692 COOH 4-Cl-phenyl —CH₂—CH₂— 4-OEt-phenyl Me Me N N N O I-693 COOH4-Cl-phenyl —CH₂—CH₂— 4-OEt-phenyl ethyl Me CH N N O I-694 COOH4-Cl-phenyl —CH₂—CH₂—CH₂— 4-iPr-phenyl ethyl Me CH N N O I-695 COOH4-Cl-phenyl —CH₂—CH₂—CH₂— 3,4-methylenedioxyphenyl OMe Me CH N N O I-696COOH phenyl —CH₂—CH₂—CH₂— 2-Cl-phenyl ethyl Me CH N N S I-697 COOMephenyl —CH₂—CH₂—CH₂— 2-Cl-phenyl OMe CH₂—CH₂—CH₂—C N N O I-698 COOHphenyl —CH₂—CH₂—CH₂— 3,5-di-OMe-4-Cl-phenyl OMe Me CH N N O I-699 COOH4-Cl-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl OMe Me CH N N O I-700 COOH4-Cl-phenyl —CH₂—CH₂— 3,4-di-OMe-phenyl Me Me CH N N O I-701 COOH4-Cl-phenyl —CH₂—CH₂—CH₂— 3-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-702 COOH4-Et-phenyl —CH₂—CH₂—CH₂— 4-OMe-phenyl ethyl Me CH N N O I-703 COOHphenyl —CH₂—CH₂—CH₂— 3,5-di-OMe-4-Cl-phenyl Me Me CH N N O I-704 COOHphenyl —CH₂—CH₂— 4-iPr-phenyl CF₃ Me CH N N O I-705 COOH phenyl—CH₂—CH₂— 4-iPr-phenyl OMe Me CH N N O I-706 COOH phenyl —CH═CH—CH₂—4-OMe-phenyl OMe Me CH N N S I-707 COOMe phenyl —CH═CH—CH₂— 4-OMe-phenylMe Me CH N N O I-708 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂— 4-OEt, 3-OMe-phenylOMe O—CH₂—CH₂—C N N O I-709 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂— 4-iPr-phenylMe Me N N N O I-710 COOH 4-Cl-phenyl —CH₂—CH₂— 4-Me-phenyl OMe Me CH N NO I-711 COOH 4-Cl-phenyl —CH₂—CH₂— 4-Me-phenyl Me Me CH N N O I-712 COOHphenyl —CH═CH—CH₂— 4-OMe-phenyl Me Me N CH N O I-713 COOH phenyl—CH₂—CH₂— 4-Cl-phenyl Me Me CH N N O I-714 COOH phenyl —CH₂—CH₂—4-Cl-phenyl Me Me N N N O I-715 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂—3-OMe-phenyl Me Me N N N O I-716 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂—3-OMe-phenyl ethyl Me CH N N O I-717 COOH phenyl —CH═CH—CH₂—3-Cl-4-OMe-phenyl ethyl Me CH N N O I-718 COOH phenyl —CH═CH—CH₂—3-Cl-4-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-719 COOH phenyl —CH₂—CH₂—phenyl OMe Me CH N N O I-720 COOH phenyl —CH₂—CH₂— phenyl Me Me CH N N OI-721 COOH 4-F-phenyl —CH═CH—CH₂— 3,4-di-OMe-phenyl OMe Me CH N N OI-722 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂— 4-SMe-phenyl OMe O—CH₂—CH₂—C N N OI-723 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂— 4-OEt, 3-OMe-phenyl OMe Me CH N N OI-724 COOH 4-Cl-phenyl —CH₂—CH₂— 4-OEt-phenyl OMe Me CH N N O I-725 COOH4-Cl-phenyl —CH₂—CH₂— 4-OEt-phenyl Me Me CH N N O I-726 COOMe phenyl—CH═CH—CH₂— 3,4-di-OMe-phenyl Me Me CH N N O I-727 COOH phenyl—CH═CH—CH₂— 3,4-di-OMe-phenyl Me Me N CH N O I-728 COOH phenyl—CH═CH—CH₂— 3,4-di-OMe-phenyl OMe O—CH₂—CH₂—C N N S I-729 COOH4-Cl-phenyl —CH₂—CH₂—CH₂— 3-OMe-phenyl OMe Me CH N N O I-730 COOH4-Cl-phenyl —CH₂—CH₂—CH₂— 3-OMe-phenyl Me Me CH N N O I-731 COOH4-Cl-phenyl —CH₂—CH₂— 4-OMe-phenyl ethyl Me CH N N O I-732 COOH4-Cl-phenyl —CH₂—CH₂— 4-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-733 COOHphenyl —CH═CH—CH₂— cyclohexyl OMe Me CH N N O I-734 COOH phenyl—CH₂—CH₂— 4-OEt-3-OMe-phenyl OMe CH₂—CH₂—CH₂—C N N O I-735 COOH phenyl—CH₂—CH₂— 4-OEt-3-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-736 COOH4-Cl-phenyl —CH₂—CH₂—CH₂— 4-SMe-phenyl Me Me N N N O I-737 COOH4-Cl-phenyl —CH₂—CH₂—CH₂— 4-SMe-phenyl ethyl Me CH N N O I-738 COOHphenyl —CH═CH—CH₂— cyclohexyl Me Me CH N N O I-739 COOH phenyl—CH═CH—CH₂— 4-Me-phenyl Me Me N N N S I-740 COOH 4-Cl-phenyl —CH₂—CH₂—3,4-methylenedioxyphenyl ethyl Me CH N N O I-741 COOH 4-Cl-phenyl—CH₂—CH₂— 3,4-methylenedioxyphenyl OMe O—CH₂—CH₂—C N N O I-742 COOHphenyl —C(phenyl)═CH—CH₂— phenyl OMe Me CH N N O I-743 COOH 4-Cl-phenyl—CH₂—CH₂—CH₂— 3,5-di-OMe-phenyl OMe Me CH N N O I-744 COOH 4-Cl-phenyl—CH₂—CH₂—CH₂— 3,5-di-OMe-phenyl Me Me CH N N O I-745 COOH phenyl—CH₂—CH₂— 4-Cl-phenyl CF₃ Me CH N N O I-746 COOH phenyl —CH₂—CH₂—4-Cl-phenyl OMe Me CH N N O I-747 COOH 4-F-phenyl —CH═CH—CH₂— phenyl MeMe CH N N O I-748 COOH 4-F-phenyl —CH═CH—CH₂— phenyl Me Me N N N O I-749COOH phenyl —CH₂—CH₂— 4-OEt-3-OMe-phenyl Me Me N N N O I-750 COOH4-Cl-phenyl —CH₂—CH₂—CH₂— 4-SMe-phenyl OMe Me CH N N O I-751 COOH4-Cl-phenyl —CH₂—CH₂—CH₂— 4-SMe-phenyl Me Me CH N N O I-752 COOH phenyl—CH₂—CH₂— 4-OEt-3-OMe-phenyl ethyl Me CH N N O I-753 COOH phenyl—C(phenyl)═CH—CH₂— phenyl ethyl Me CH N N O I-754 COOH 4-Cl-phenyl—CH₂—CH₂— naphth-2-yl ethyl Me CH N N O I-755 COOH 4-Cl-phenyl —CH₂—CH₂—naphth-2-yl OMe O—CH₂—CH₂—C N N O I-756 COOH phenyl —CH═CH—CH₂— phenylOMe O—CH₂—CH₂—C N N S I-757 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂— 4-OEt-phenylMe Me CH N N O I-758 COOH 4-Cl-phenyl —CH₂—CH₂—CH₂— 4-OEt-phenyl ethylMe CH N N O l-759 COOH phenyl —CH₂—CH₂—CH₂— 4-OEt-phenyl CF₃ Me CH N N OI-760 COOH phenyl —CH₂—CH₂—CH₂— 4-OEt-phenyl OMe Me CH N N O I-761 COOH4-Cl-phenyl —CH₂—CH₂— 4-OMe-phenyl Me Me CH N N O I-762 COOH 4-Cl-phenyl—CH₂—CH₂— 4-OMe-phenyl Me Me N N N O I-763 COOH 4-Cl-phenyl—CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl ethyl Me CH N N O I-764 COOH 4-Cl-phenyl—CH₂—CH₂—CH₂— 3,4-di-OMe-phenyl OMe O—CH₂—CH₂—C N N O I-765 COOH phenyl—CH₂—CH₂—CH₂— 4-OEt-phenyl Me Me CH N N O

Example 16

Receptor binding data were measured by the binding assay described abovefor the compounds listed hereinafter.

The results are shown in Table 2.

TABLE 2 Receptor binding data (K_(i) values) Compound ET_(A) [nM/l][sic] ET_(B) [nM/l] [sic] I-116 35 35 I-140 575 460 I-146 4 29 I-321 340290 I-355 132 82 I-370 11 54 I-445 3.5 7.2 I-445 (S) enantiomer 1.3 4.1I-445 (R) enantiomer 65 140 I-482 2 14 I-499 31 135 I-585 6 23 I-593 300160 I-622 3 23 I-635 210 126 I-672 60 185 I-699 230 130 I-713 20 96

We claim:
 1. A carboxylic acid compound of the formula I

where R¹ is a group

where R is a radical OR⁷ where R⁷ is hydrogen, the cation of an alkalimetal, the cation of an alkaline earth metal or a physiologicallytolerated organic ammonium ion; R² is hydrogen, hydroxyl, NH₂,NH(C₁-C₄-alkyl, N(C₁-C₄-alkyl)₂, halogen, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₂-C₄-alkynyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy orC₁-C₄-alkylthio; X is nitrogen; Y is nitrogen; Z is CR¹⁰, where R¹⁰ ishydrogen or C₁-C₄-alkyl; R³ is hydrogen, hydroxyl, NH₂, NH(C₁-C₄-alkyl),N(C₁-C₄-alkyl)₂, halogen, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl,C₁-C₄-hydroxyalkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy orC₁-C₄-alkylthio, or CR³ is linked to CR¹⁰ as indicated above to give a5- or 6-membered ring; R⁴ and R⁵, which may be identical or different,are phenyl or naphthyl, unsubstituted or substituted; R⁶ is substitutedphenyl; W is oxygen; Q is a spacer whose length corresponds to that of aC₂-C₄ chain, or the physiologically tolerated salts, and theenantiomerically pure and diastereoisomerically pure forms thereofwherein the compound has an ET_(A):ET_(B) affinity ratio of greater than0.1 and less than
 20. 2. A pharmaceutical preparation for peroral,parenteral or intraparenteral use, comprising at least one carboxylicacid compound as claimed in claim 1, and conventional pharmaceuticalancillary substances.
 3. The method of treating a disease selected fromthe group consisting of chronic heart failure, restenosis, high bloodpressure, pulmonary hypertension, acute/chronic kidney failure, cerebralischemia, asthma, benign prostate hyperplasia and prostate cancercomprising administering an effective amount of a compound of claim 1 toa patient in need of such treatment.
 4. The method of claim 3 furthercomprising administering inhibitors of the rennin-angiotensin systemmixed ACE/neutral endopeptidase (NEP) inhibitors and/or β blockers. 5.The carboxylic acid derivative of claim 1, wherein Q is C₂-C₄-alkyl,C₃-C₄-alkenyl, C₃-C₄-alkynyl, —S—CH₂—CH₂—, or —O—CH₂—CH₂—, each of theseradicals being unsubstituted or substituted one or more times byhalogen, hydroxyl, mercapto, carboxyl, C₁-C₄-alkyl, C₁-C₄-alkoxy,C₁-C₄-alkylthio, or phenyl which is unsubstituted or substituted one ormore times by halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio; or Q forms togetherwith R⁶ 2-indanyl, 3-indanyl, 1,2,3,4-tetrahydro-2-naphthyl, or1,2,3,4-tetrahydro-3-naphthyl, it being possible for the phenyl rings ineach case to be substituted by halogen, hydroxyl, mercapto, carboxyl,cyano, C₁-C₄-alkoxy, C₁-C₄-alkyl, C₂-C₄-alkynyl, C₃-C₆-alkenyloxy,C₃-C₆-alkynyloxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy,C₁-C₄-alkoxycarbonyl, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂ or phenyl.